New 1-heteroacyl-3-indolyl aliphatic acids



Patented 1 a 2 l M may be OH, NH lower alkoxy, benzyloxy, OZ where 3,201,414

e Z is a cation or OY where Y is the structure: NEW l-HETEROACYL-Ii-INDOLYL I ALIPHATIC ACIDS V f Tsung-Ying Shen, Westfield, N.J., assignor to Merck & R,- oH-C Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed July 22, 1963, Ser. No. 296,451

16 Claims. (Cl. 260319) R N 4 This application is a continuation-in-part of my coe pending application, Serial No. 164,615, filed January R1 1962, now a n Whic11 Was a Continuation-h1- In the most preferred compounds of the invention, R P of y appllcatloll, 561131 4, filed March 22, is a lower alkyl, lower alkoxy, nitro, amino, or substituted 1961, now abandoned. amino. Examplesof the alkyl and alkoxys are methyl, This invention relates to new chemical compounds. ethyl; propyl, t-butyl, methoxy,ethoxy, i-propoxy, and the More particularly, it relates to a new class of compounds 15 like. R is not limited to this class of substituents, how of the mdole series. Still more particularly, it is conever, and ay, if de ired, represent substituent such as cerned with new u-(3-indolyl)-lower aliphatic acids havh d aryl, ary-lcxy, hydroxy, mercapto, halo, mg an aromatic carboxylic acyl radical of the structure: pseudohalo such as 0P CHF or other haloalkyls, nitro,

Q amino, alkylamino, acylamino, haloalkyl, cyano, sul- H c V famyl, sulfoxide, aminomethyl, substituted aminomethyl,

carboxy, carboalkoxy groups. 7 X A critical feature of the new compounds described herein is the presence of a heteroaroyl radical attached to the N-l position of the indole. These acyl groups may be further substituted in the aromatic ring with hydrocarbon groups such as lower alkyl (methyl, ethyl, propyl), 10wer cycloalkyl such as cyclopentyl or cyclo'hexyhphenyl, substituted phenyl, such as lower alkoxyphenyl, and 'halogenophenyl, aralkyl such as benzyl and phenethyl (collectively phenyl lower alkyl) and the like. It may also be a heterocyclic substituent such as furyl or pyridyl in which X may be 0, S or NH and which ring can be further substituted attached to the nitrogen atom of the indole ring. It is concerned further with salts, esters and amide derivatives of such compounds. It relates also to certain new heterocyclic acids usable in the preparation of the above compounds.

The new aroyl and heteroaroyl indolyl aliphatic acid compounds of this invention have the general structural formula' or asubstituted lower alkyl such as lower alkanoyl lower 33 7 alkyl, lower alkoxy lower alkyl or cyanomethyl. A

7 R JH-OOM The N-l acyl group may also carry functional sub- 7 I v stituents. Thus, suitable aroyl substituents are the thenoyl,

\ R1 'furoyl and pyrrole carbonyl groups. The aromatic rings R4 l of such acyl groups may contain any of the above sub- =0 stituents. In the preferred compounds they contain at least one functional substituent. This substituent may be V y 40 a hydroxy or an etherified hydroxythydroc-arbonoxy) in which R may be a thiophene,-furan, pyrrole or a subgroup such as a lower alkoxy, e.g., methoxy, ethoxy, iso

stituted thiophene, furan or pyrr'ole radical in which propoxy, propoxy, an alkenyloxy such as allyloxy, an

the substituents may be halogen, lower alkyl, lower aryloxy or aralkoxy group, e.g., phenoxy, benzyloxy,

alkylthio, lower alkoxy, mono-fluoromethyl, difluorohalobenzyloxy, lower alkoxybenzyloxy andthe like. It

methyl, trifluoromethyl, phenyl, phenoxy, lower cyclomay be a nitro radical or a halogen such as chlorine,

alkyl, lower alkoxyphenyl, halogenophenyl, furyl, bromine, iodine or fluorine. Further, it may be a merpyridyl, phenyl lower alkyl, lower alkanoyl lower alkyl, capto or a substituted mercapto radical of the type exlower alkoxy lower alkyl, lower alkeny, benzoyl, cyanoemplified by alkylthio groups such as methylthio, ethylmethyl, di(lower alkyl) sulfamyl, lower alkanoyl, di thio, and propylthio and arylthi-o groups, e.g., phenyl-thio. (lower alkyl) carboxamido, cyano, carb-lower alkoxy, Other "sulfur containing functional substituents include lower alkoxyphenylsulfonyl, lower alkyl sulfonyl, loweralkoxyphenylsulfinyl such as p-methoxyphenylsulphenylthio, benzylthio-lower alkyl, benzyl :sulfonyl finyl, benzylthio lower alkyl'such as'benzylthiomethy-l,

' lower alkyl, lower alkylthio lower alkyl, nitro, amino, benzyluslfonyl lower alkyl such as benzylsulfonylmethyl, lower alkylamino, di(lower alkyl) amino, benzyloxylower alkylthio lower alkyl such as-methylthiomethyl and lower alkyl, lower alkanoylamino, furfurylthio-lower the like. The N-l aroyl radical may, if desired, be haloalkyl, lower alkanoylamino, hydroxy and benzyloxy; V alkylated, as with monofiuoromethyl, difiuoromethyl, tri- R2 may be hydrogen, lower alkenyl or lower alkyl; fluoromethyl, trifluoroethyl, perfluoroethyl, j8-chloroethyl R may be hydrogen, lower alkoxy, fluorine, lower alkyl or like substituent, acylated as with acetyl, propionyl, or trifluoromethyl; V V a benzoyl, phenylacetyl, trifluoroacetyl and like acyl groups,

R may be hydrogen, lower alkyl, lower alk-oxy, nitro, or it may containa haloalkoxy'or haloalkylthio substituamino, lower alkylamino, di(lower alkyl)amino, lower en-t; In addition, the invention embraces compounds alkanoylamino, lower alkanoyl, lower alkylamino, biswherein the aroyl radical contains sulfamyl, benzy-lthio- (hydroxy lower alkyl)amino, l-pyrrolidino, 4-methylmethyl, cyano, sulfonamido or diloweralkylsulfonamido l-piperizinyl, 4morpholinyl, cyano, amino lower alkyl, radical; it may contain a carboxy substituent, ora deriv di(lower alkyDamino lower alkyl, trifluoromethyl, ative thereof, such'as an alkali metal'salt or alower halogen, di(lower alkyl)sulfamyl, benzylthio, lower alkyl ester of the carboxy radical, an aldehyde,- azide, alkylbenzylthio, lower alkoxy benzylthio, halogenoamide, hydrazide and the like, or an aldehyde derivative benz ylthio, benzyloxy, loweralkylbenzyloxy, lower of-the type represented by acetals or thio acetals. In v alkoxy benzyloxy, halogenobenzyloxy, lower alkenyl, the preferred compounds, the -N-l aroyl radical isthenoyl lower alkenyloxy, l-azacyclopropyl, cyclopropyland the functional substituent is in the 5-position of the methyloxy or cyclobutylmethyloxy; and ring. e p v s j c3 5% The new heterocyclic acids which form an additional embodiment of this invention may be represented by the formula:

in which Y is O or S and A is diloweralkylcarbamide, diloweralkylsulfamyl, or mono, di or trifluoromethyl.

The a-(3-indolyl)-ali-phatic acids described herein are preferably lower aliphatic acids such as or-(3-indolyl) derivatives of acetic, propionic, butyric, valeric and like acids. Lower alkyl esters, salts and the amides of such aliphatic acids represent an additional aspect of the invention. The esters are important intermediates in the synthesis of the free acids, and in many cases are themselves of importance as end products. The preferred esters are the lower alkyl esters such as the methyl, ethyl, propyl or t-butyl compounds and the benzyl, p-halobenzyl and like esters.

The salts of these new a-(l-aroyl or heteroaroyl-3-indolyl)-lower aliphatic acids can be obtained by treatment of the free acid with base under mild conditions. In this manner there may be obtained alkaline metal salts such as the sodium and potassium, the aluminum or magnesium salts or salts of alkaline earth metals, examples of which are barium and calcium. Salts of organic amines such as dimethylamine, morpholine, methyl cyclohexylamine or glucosamine may be obtained by reacting the acid with the appropriate organic base. The amides included within this invention are conveniently synthesized by first preparing the amide of an a-(3-indolyl)-lower aliphatic acid unsubstituted at the 1-position and then acylating said compound by the process described hereinbelow. Such amides are conveniently obtained by reacting the free acid with urea or treating the appropriate cid chloride with ammonia.

The 2-position of the indole ring nucleus (R in the above formula) may be hydrogen although it is preferred that there be present :at this position of the molecule a hydrocarbon radical having less than nine carbon atoms. Lower alkyl groups such as methyl, ethyl, propyl or butyl are the most satisfactory, but lower alkenyl radicals also can be used.

The following compounds are representative of those contemplated by this invention and which may be prepared by the procedure discussed hereinbelow:

Methyl-ct-[1(S-chloro-Z-thenoyl)-2-methyl-5-methoxy- S-indolyl] acetate, methyl-DA1-(5-chloro-2-furoyl)-2,5- dimethyl-3 -indolyl] -acetate, methyl-w 1- S-methylthio-Z- tbenoyl) -2-methyl-5-met-h0xy-3 -indolyl] acetate, 11- 1-( 4, 5-dichloro-2-thenoyl)-2-methyl-5-methoxy-3-indolyl]-propicnic acid, a-[1 (4-methoxypyrrolyl-2-carboxy)-2-methyl-S-methoxy-B-indolyl] aacetamide, OL-[ l-(3-thenoyl) 2 methyl-5-methoxy-3-ind0lyl]-acetarnide, ethyl ot-[1(2,5 dimethyl-3-furoyl)42-methyl-5-methoxy-3-indolyl] propionate, benzyl-u-[l-(5-acetyl -2- furoyl) 2 methyl-S-methoxy-3-indolyl]-acetate, and the like.

The x-(1-heteroaroyl-3-indolyl)-lower aliphatic acids and derivatives thereof described herein are synthesized by acylation of the a-(B-indolyD-lower aliphatic acid, ester or amide having the desired substituents at the 2- and S-pcsitions of the ring nucleus. It is preferred to carry out the acylation on an ester or amide derivative of the lower aliphatic acid. In those cases where the free acid is desired, the ester may be converted under suitable eaction conditions to the free acid. it has been observed that the l-heteroaroyl substituents is easily hydrolyzed under conditions normally employed for saponification of an ester to the free acid. For this reason, care must be taken in converting the ct-(l-heteroaroyl-E-indolyl)- lower aliphatic acid esters to the corresponding free acids. It has been found that one convenient method of accomplishing this conversion comprises acylation of the benzyl ester and subsequent hydrogenolytic removal of the benzyl ester. Alternatively, other esters such as the t-butyl esters, which are amenable to selective removal by other treatment, such as heating above 2l0 C. or by heating at 25l10 C. in the presence of a catalytic amount of an aryl sulfonic acid or other acids may be utilized. When, instead of 18.11 ester, the amides of these acids are prepared, the free acids are formed by reaction of the amides with a stoichiometric quantity of nitrous acid in an inert solvent.

The acylation reaction is preferably conducted by treating the m-(3-indolyl)-lower aliphatic acid starting material with an alkali metal hydride such as sodium hydride to form, e.g., a sodium salt and then intimately contacting said salt with a heteroaroyl acid halide in an anhydrous solvent medium. It is preferred to employ solvents such as dimethylformamide, dimethylformamide-benzene, benzene, toluene or xylene. It is preferred to carry out the acylation at about room temperature although lower temperatures may be employed if the particular reactants are unduly susceptible to decomposition.

An alternative method of acylating the 1-position is by use of a phenolic ester of the acylating acid, such as the p-nitrophenyl ester. This latter is prepared by mixing the acid and p-nitrophenol in tetrahydrofuran and adding dicyclohexyl carbodiimide in tetrahydrofurane slowly. The dicyclohexylurea which forms is removed by filtration and the nitrophenylester is recovered from the filtrate. Alternatively, there can also be used the anhydride, azide or thiophenolic ester of the acylating acid. Whichever is used, the acylation of the a-(3-indolyD-lower aliphatic acid starting material is achieved by forming a sodium salt of said material with sodium hydride in an anhydrous solvent and adding the nitrophenylester.

The ot-(l-heteroaroyl-3-indolyl)-lower aliphatic acid compounds of this invention have a high degree of antiinflammatory activity and are effective in the prevention and inhibition of granuloma tissue formation. Certain of them possess this activity in high degree and are of value in the treatment of arthritic and dermatological disorders and in like conditions which are responsive to treatment with anti-inflammatory agents. In addition, the compounds of this invention have a useful degree of antipyretic activity. For these purposes, they are normally administered orally in tablets or capsules, the optimum dosage depending, of course, on the particular compound being used and. the type and severity of infection being treated. Although the optimum quantities of these compounds of this invention to be used in such manner will depend on the compound employed and the particular type of disease condition treated, oral dose levels of preferred compounds in the range of 1.020(l0 mg. per day are useful in control of arthritic conditions, depending on the activity of the specific compound and the reaction sensitivity of the patient.

The indolyl aliphatic acid compounds employed as starting material in the reaction discussed above, and having the formula:

CHCOE where R R R and R have the previously defined meanings and E is a hydrocarbonoxy radical having less than nine carbon atoms or -NH= may be synthesized in various ways. When R is hydrogen or methyl, it is preferred to form such compounds by reacting toget. er an appropriately substituted phenylhydrazine and a substituted levulinic ester or amide to form an intermediate Rs II mQ-mnr 1+ RzOCHzlHCOE where R R R and E are as above, and R is hydrogen or methyl. The reaction is normally carried out in a lower alkanol such as methanol, ethanol, isopropanol or butanol containing an acid such as hydrochloric, hydrobromic, sulfuric or acetic acid or in aqueous mineral acid such as concentrated hydrochloric, hydrobromic, sulfuric or acetic acid, or other Lewis acids such as ZnCl BF SnCL, and the like. The acid serves as a catalyst in the condensation and ring closure reactions leading to the l-unsubstituted indole. When the substituted levulinic esters are used, the nature of the ester is not critical, although it is preferred to utilize a lower alkyl ester, e.g., the methyl, ethyl, propyl, isobutyl or isopropyl compound. To avoid the possibility of transesterification the alcohol used as the solvent medium is preferably the same as the alcohol moiety of the ester. When R is hydrogen, it is convenient to employ the aldehyde in the form of an acetal, e.g., methyl 'y,' -dimethoxy butyrate. An acid matography and/or distillation. Since the l-unsubstituted esters are low melting solids, they are conveniently purified by distillation under reduced pressure. They are saponified by treatment with an alkali metal hydroxide.

The substituted phenylhydrazines employed as one of the starting materials in this synthesis are prepared by known methods. One convenient method is by diazotization of the appropriately substituted aniline to give the diazo compound, treatment of the latter with stannous chloride to form a tin complex, and decomposition of this complex to the phenylhydrazine with sodium hydroxide. The l-acyl group in ot-(1-acyl-3-indolyl) aliphatic acids and esters of this invention are, as has been mentioned earlier, easily hydrolyzed under the conditions normally used to saponify an ester. For this reason, the benzyl ester of the intermediate oc-'(1-unsubstituted-3-indolyl) acids are a convenient starting material. These are obtained by forming the free a-(1-unsubstituted-3-indolyl) aliphatic acid and esterifying this with benzyl alcohol in an inert solvent with an acid catalyst (sulfuric, aryl sulfonic acids, etc.). Alternatively, the intermediate benzyl ester is synthesized directly by using the benzyl ester of the proper levulinic acid in the original synthesis of the indole ring, or is formed by base catalyzed ester exchange from other esters. After acylation of the indole nitrogen of these benzyl ester intermediates, the btnzyl group can be removed clearly by hydrogenolysis, a process which leaves the l-acyl group untouched.

6 Alternatively, it is possible first to produce an indole of the formula:

where R R and R have the same meaning as before, and then to introduce the carboxylic acid residue at the 3-position. This is .accompished by treating the indole of the above formula under Manni-ch reaction conditions with formaldehydedialkylamine to produce a substituted gramine, subsequently reacting this latter compound with an alkali metal cyanide in a lower alkanol, and finally hydrolyzing with a strong base such as sodium or potassium hydroxide.

While this method of introducing the aliphatic acid residue at the 3-position after elaboration of the indole ring is, of course, generally applicable to compounds having the structure shown above, it is particularly useful for making compounds of this invention wherein R is an alkyl radical other than methyl, such as the 2-ethyl, 2-propyl, 2-allyl and like substances. Compounds of the above formula, unsubstituted in the 3-position, are readily prepared following the procedures set forth in column 2 and 3 of U.S. Patent No. 2,825,734. Products where R is acyloxy, halo, cyano, carboxy, carbalkoxy, alkyl, aryl, aralkyl, nitro or hydrocar bonoxy are prepared via the synthesis beginning from a substituted 2-nitro benzaldehyde or Z-nitrotoluene.

The synthesis of various compounds of this invention having on the indole ring system a S-substituentwhich has a nitrogen attached to the homocyclic ring of the indole is generally based on the S-nitro compound. This is transformed into the desired S-Substituent. Such transformation may be before or after acylation of the l-position, depending on the extent to which the desired 5-substituent may interfere with the acylation. If such interference is possible, the l-acylation should be carried out on the 5-nitro indole and the nitro later transformed into the desired S-substituent. Such transformation can be carried out in a number of ways. Reduction of the S-nitro groups gives a S-amino group. Reaction of the amino with alkyl halides gives mono and dialkyl amino groups. If the alkyl halide is a dihaloalkylene group (e.g., 1,4-'di bromobu-tane) .a heterocyclic ring (e.g., pyrr-olidino) is formed. Similarly, bis(B-chloroethyl)ether will give an N-morpholino compound. Alkylation can also be carried out simultaneous with reduction, as, e.g., with formaldehyde and Raney nickel and hydrogen.

Acylation can similarly be carried out on the S-amino 7 compounds or on the S-nitro -(with simultaneous reduction) to give S-acylamido compounds. TheS-amino group can be reacted with isocyanates to give S-ureido compounds.

Example 1 A. ETHY L-a- (2-METHYL fi-METHOXYS-TNDOLYL) PROP-IONATE A solution of 25 g. of p-methoxyphenylhydrazine hydrochloride and 20 g. of ethyl a-methyl levulinate in 250 ml. of 2 N ethanolic hydrochloride is heated on a steam bath for a few minutes. An exothermic reaction takes place with the separation of ammonium chloride. The reaction flask is removed from the steam bath and the mixture allowed to reflux gently until the initial reaction subsides. The mixture is again heated on a steam bath under reflux for 30 minutes, and then concentrated in vacuo to a volume of about ml. The concentrate is diluted with about 400 ml. of Water and extracted with ether. The resulting ethereal extract is washed with a saturated solution of sodium bicarbonate, and with water, and dried over anhydrous sodium sulfate. The dried solution is filtered and evaporated to a dark brown syrup which is purified by chromatography over about 1 lb. or" acid-Washed alumina in a 2%" ID. column using mixtures of ether and petroleum ether (v./v. 1:9 to 1:1) as eluent. The light yellow syrup so obtained is distilled in a short-path distillation apparatus and the product collected at B.'P. 150153 C. (0.25 mm) The distillate of ethyl o: (2-methyl-5-methoxy-3-indoyl)-propionate crystallizes on trituration with petroleum ether, M.P. 53-55 .5 C. On recrystallization from a mixture of ether and petroleum ether the melting point is unchanged.

Calcd. for C l-I O N: C, 68.94; H, 7.33; N, 5.36. Found: C, 69.23; H, 7.31; N, 5.60.

When the methyl, propyl, isopropyl or benzyl ester of a-In thyl levulinic acid is employed in the above reaction in place of the ethyl ester, there is obtained methyl-o:- 2-methyl-5-methoxy-3 -indolyl -propion ate, propyl-e- 2- methyl 5 methoxy-3-indolyl)-propionate, lSOPl'OPYl-Ct- (2methyl-5-methoxy-3-indolyl)-propionate, or benzyl-a- (2-methyl-5-methoxy-3-indoly1)-propionate, respectively. Alternatively, When an ester of levulinic acid is used as starting material in the above process, the corresponding ester of u-(2-rnethyl5-methoxy-3-indolyl)-acetic acid is obtained.

B. ETHYL-a-(2,d-DIMETHYL-S-INDOLYL) PROP-IONATE 20 g. of p-methylphenylhydrazine hydrochloride and 20 g. of ethyl IZ-II16thYl levulinate are added to 250 ml. of 2 N ethanolic hydrogen chlorid and the mixture warmed until reaction sets in. After the initial exothermic reaction stops, the mixture is refluxed for about /2 hour and then concentrated in vacuo to about /3 volume. 400 ml. of water are added and the aqueous solution extracted with ether. The ether extracts are washed with sodium bicarbonate solution, and with Water, then dried over sodium sulfate. The ether solution is concentrated to a small volume in vacuo and chromatographed over acid washed alumina (1 lb. of aluminia in a 2 /2 ID. column). The material eluted with ether-peroleum ether (v./v.9:1 to 1:1) is distilled in a short-path distillation apparatus. Ethyle-(2,5-dimethyl-3-indolyl)-propionate distills at 150-170 (bath temp.)/1 mm., and crystallizes on trituration with petroleum ether, M.P. 88-885 C.

When a lower alkyl or benzyl levulinate is employed in place of ethyl a-methyl levulinate, lower alkyl or benzyl- (2,5-dimethyl-3-indolyl)-actetate is produced.

EXAMPLE 2 A suspension of 2.3 g. (0.046 m.) of 50% sodium hydridemineral oil in 250 ml. of dimethylformamide is stirred for 20 minutes under nitrogen with ice-cooling. Then 8.64 g. (0.035 m.) of ethyl -a-(2-methyl-5-methoxy- 3-indolyl)-propionate is added and the mixture stirred for 20 minutes. 6.7 g. (0.046 m.) of 2-thenoyl chloride in 50 ml. of dimethylformamide is added dropwise over a period of 30 minutes. The mixture is stirred in an ice-bath for 5 hours under nitrogen. It is then poured into a mixture of 500 ml. of ether, 5 ml. of acetic acid and 1 l. of iced water. The organic products are extracted with 3 x 300 ml. of ether. The ether solutions are combined and washed with a large quantity of water, and dried over sodium sulfate. The solution is filtered, evaporated to near dryness and the residue charged onto a 300 g. alumina column. The ethyl-H1-(2-thenoyl)-2- methyl--methoxy-3-indoly1]apropionate is eluded with ether in petroleum ether. It is obtained as a yellow oil on concentration of the eluates to dryness.

The thenoyl chloride starting material is obtained by heating a mixture of 19.2 g. (0.15 m.) of Z-thenoic acid and 21.4 g. (0.18 m.) of thionyl chloride on a steam bath for 1 hour. About ml. of benzene is then added and boiled oil". The remaining solution is concentrated and distilled to give the acid chloride, Bl. 190.

When methyl -(2-methyl-5-methoxy-3-idolyl)-acetate is employed as the starting material in the above process, there is obtained methyl-(1-thenoyl-2-methyl-5-methoxy 3-indolyl) -acetate.

EXAMPLE 3 To 3.9 g. (0.078 m.) of 51% sodium hydride-mineral oil suspended in 150 ml. of distilled dimethylformamide, in a 1 liter 3-neck flask, is added with stirring at 0 C. 9.5 g. (0.040 m.) of methyl-(2-methyl-5-methoxy-3-indolyl)-acetate in 150 ml. of dimethyl-formamide. The mixture is allowed to stir for 1 hour and then 8.8 g. (0.052) of 5-chloro-2-furoyl chloride (prepared by the action of thionyl chloride on the acid) in 50 ml. of dimethylformamide is added dropwise over a period of minutes. The reaction mixture is stirred another 30 minutes at 0 C. and then allowed to stand 12 hours in the cold.

The reaction mixture is then filtered and the solids washed with ether. The ether is added to the filtrate which is then washed with Water and dried over sodium sulfate. After filtering 01f the sodium sulfate, approximately 75 g. of acid-washed alumina is added to the ethereal solution and this mixture concentrated to dryness.

The indole-coated alumina is then packed on top of a column of 400 g. of alumina. The column is eluted with petroleum ether containing increasing amounts of ethyl ether. Methyl-cr-[1-(5-chloro-2-furoyl)-2-methyl-5-methoxy 3 indolyl] acetate is eluted with 15% etherpetroleum ether. These latter elua-tes are combined and concentrated to dryness. Recrystallization of the residue from benezene-petroleum ether yields substantially pure methyl oz [1 (5 chloro 2 furoyl) 2 methyl- 5 -methoxy-3-indolyl] -acetate.

Carrying out the above-noted process with ethyl-a-(2- methyl-5-methoxy-3-indolyl -propionate or benzyl-a- (2, 5-dimethyl-3-indolyl)-propionate yields, respectively, ethy1- a [1 (5 chloro 2 furoyl) 2 methyl 5 methoxy-3-indolyl]-propionate and benzyl-a-[l-(5-chloro-2- turoyl) 2,5-dimethyl-3 -indoly [-propionate.

EXAMPLE 4 Ethyl-a- [1(2,5 -dimethyl-3-then0yl) -2-methyl-5- metlzoxy-3-indolyl] -pr 0pi0nate A mixture of 100 ml. of dimethylformamide, 5.2 g. (0.02 m.) of ethyl-w (2-rnethyl-5-methoxy-3-indolyl)-propionate and 1.2 g. (0.025 rn.) of sodium hydride in mineral oil dispersion) is stirred in an ice-bath under nitrogen for 1 hour. A solution of 3.5 g. (0.02 m.) of 2,5-dimethyl-3-thenoyl chloride (prepared from the acid and thionyl chloride) and 25 ml. of dimethylformamide is then added during 0.5 hour, and stirring is continued for 16 hours at room temperature. The mixture is poured into 350 ml. of water, extracted with ether, and the ether solution washed with water, dried over magneisium sulfate, filtered and evaporated to dryness under reduced pressure. The residual oil is dissolved in petroleum ether (70 C.) and chromatographed on 250 g. of acid-washed alumina. The ethyl-a-[l-(2,5-dimethyl-3-thenoyl -2-methyl-5-methoxy-3-indo1yl] -pr0pi0n-ate is eluted1 with 15% ether in petroleum ether and isolated as an 01.

EXAMPLE 5 To a solution of 5.22 g. of ethyl-a-(2-methyl-5-methoxy- 3-indolyl)-propionate in 20 ml. of dimethylformamide is added a suspension of 1.2 g. of 51% sodium hydride in mineral oil in 40 ml. of dimethylformamide. After 1 hour of stirring at room temperature, a solution of 3.95 g. of 5-methoxy-2-thenoyl chloride in 10 ml. of dimethylformamide is added to initiate a mild exothermic reaction with precipitation of sodium chloride. The reaction mixture is stirred for 6 hours followed by standingovernight. The mixture is poured into about 200 g. of ice and extracted with ether three times. The ethereal solution is washed with Water, sodium bicarbonate and dried over potassium carbonate. ,After filtration the solution is evaporated to a syrup and chromatographed on a column of 100 g. of acid-washed alumina, using mixtures of benzene-petroleum ether (2:1 to 3:1 v./v.) as eluent. A total of 1.06 g. of ethyl-[l-(5-methoxy-2-thenoyl)-2- methyl-5-methoxy-3-indolyl]-propionate is obtained. The infrared spectrum shows no N-H absorption near the 2.8-3 region but shows strong 0 absorptions at 5.8 and 5.95, characteristic for ester and amide functional groups, respectively.

EXAMPLE 6 Ethy l-oz- [1 nitro-Z-furoyl -2-methyl-5 -meth0xy- 3-ind0lyl1-pr0pionate 13 g. of ethyl-(2-methyl-5-methoxy-3-indolyl)-propionate is added to a mixture of 2.5 g. of 51% sodium hydride-mineral oi'l emulsion in 240 ml. of dimethylformamide. The resulting mixture is stirred at room temperature for 30 minutes and then a solution of 8.75 g. of 5- EXAMPLE 7 1 (3,4,5-trimethyLZ-thenoyl) -2methyl-5-meth0xy-3- indolyl acetic acid A. A solution of g. of methyl-(2 methyl 5-methoxy- 3-indolyl)-acetate and 0.2 g. of sodium in 60 ml. of benzyl alcohol is slowly fractionated over a period of 4 hours through a Vigreux column to remove methanol. The excess benzyl alcohol is then removed by distillation at 60 C. (2.5 mm.) to give a residue of 18.6 g. of benzyl- (2-methyl-5-methoxy-3 -indolyl -acetate. V

B. 10 g. of benzyl ester obtained above is added to 3.3 g. of 51% sodium hydride-mineral oil emulsion in 260 ml. of dimet-hylformamide according to the procedure of Example 2. This mixture is treated as described in that example in 6.4 g. of 3,4,5-trimethyl-2-thenoyl chloride (prepared from thionyl chloride and the acid) and the reaction mixture worked up by the above-described process using a chromatographic column of 340 g. of alumina and eluting with 2(l30% ether in petroleum ether. From these eluates there is obtained benzyl-[l- (3,4,S-trimethyl-Z-thenoyl)-2-methyl 5 methoxy 3 in dolyl]-acetate, M.P. 9192 C.

C. 1.5 g. of the ester obtained in Part '13 above is added to ml. of ethyl acetate containing a drop of acetic acid and reduced catalytical-ly at room temperature in the.

presence of palladium on charcoal catalyst. When the reduction is complete the catalyst is removed by filtration and the filtrate evaporated to a crystalline residue. This residue is recrystallized from aqueous ethanol to give 1- (3,4,5 trimethyl 2 thenoyl) 2 methyl 5 methoxy- 3-indolyl acetic acid. Alternatively, the residue obtained on removal of the reaction solvent may be purified by dissolving in chloroform and precipitating by addition of petroleum ether to the chloroform solution.

1 9 EXAMPLE 8 Ethyl-ll- [1 -(2-methyl-5 -br0m0-3-fur0yl -2-methyl-5 methoxy-3-ind0lyl] -pr0pi0nate 10.5 g. of ethyl-a-(2-methyl-5-methoxy-3-indolyl)-propionate is added to a suspension of 2.2 g. of 51% sodium hydride-mineral oil emulsion in 240 ml. of dimethylformamide. After stirring for 25 minutes, 7.5 g. of 2- methyl-S-bromo-3-furoyl chloride (prepared from thionyl chloride and the acid) is added thereto slowly over a 40- rninute period, and the resulting mixture stirred for 40 minutes at lO-l5 C; The reaction mixture is then poured into 400 ml. of water and the product isolated as described in Example 4 to give substantially pure ethyl- 0t [11 (2 methyl 5 bromo 3 furoyl) 2 methyl- 5 -rnethoxy-3 -indolyl] -propionate.

EXAMPLE 9 The corresponding N-l aroyl or heteroaroyl derivatives of benzyl-w(2-methyl-5-methoxy-3-indolyl) propionate and benzyl-(2-methyl-S-methoxy-B-indolyl)-acetate are B-methyl-Z-therioyl chloride 4-methyl-2-thenoyl chloride 4-rnethyl-3-thenoyl chloride S-methyl-Z-thenoyl chloride S-methyl-S-thenoyl chloride 5-ethyl-2-thenoyl chloride S-t-butyl-Z-thenoyl chloride S-phenyl-Z-thenoyl chloride 3,4-diphenyl-2-then0yl chloride 5-ot-phenylethyl-2-thenoyl chloride 5-chloro-2-thenoyl chloride 3-bromo-2-thenoyl chloride 4-bromo-3-thenoyl chloride 3-iodo-2-thenoyl chloride 3,4,5-trichloro-2-thenoyl chloride 5-methyl-3,4-dibromothenoyl chloride 5-acetyl-3-thenoyl chloride 2,5-dimethyl-4-acetyl thenoyl chloride S-methylthio-Z-thenoyl chloride S-isobutylthio-Z-thenoyl chloride 2-methylthio-5-methyl-3thenoyl chloride 4-methylsulfonyl-Z-thenoyl chloride 5-methylsulfonyl-Z-thenoyl chloride 5-p-methoxyphenylsulfonyl-Z-thenoyl chloride S-cafbomethoxy-Z-thenoyl chloride 5-allyl-2-thenoyl chloride 5-ethyl-2-furoyl chloride 4-t-butyl-2-furoyl chloride 3,5-dimethyl-2-furoyl chloride 5= l-methylcyclohexyl) -2-furoyl chloride 2-methyl-5-phenyl-3-furoyl chloride Z-methyl-5-p-methoxyphenyl-3-furoyl chloride 3,4-diphenyl-2-furoyl chloride S-(Z-furyD-Z-furoyl chloride S-benz'yl-Z-furoyl chloride S -furfuryI-Z furoyI chloride 5 bromo-2-furoyl chloride 4-methoxy-S-methyl-Z-furoyl chloride 3,4-dimethoxy-Q-furoyl chloride 5 cyclohexyloxy-2-furoyl chloride 3-cyano-2-furoyl chloride 5-methyl-'4-acetyl-2-furoyl chloride S-forrnyl-Z-furoyl chloride 5 ohloroA-t-butyl-2-furoyl chloride 5-formyl-2-phenyl-3-furoyl chloride S-ethoxymethylQ-furoyl chloride S-methoxymethyl-Z-furoyl chloride 1 1 -acetonyl-2-methyl-3-furoyl chloride 5-benzyloxymethyl-Z-furoyl chloride 5-benzylthiomethyl-Z-furoyl chloride 5-furfurylthi'ornethyl-2-furoyl chloride 5-benzylsulfonylmethyl-Z-furoyl chloride 5-butylthiomethyl-2-furoyl chloride S-phenoxy-Z-furoyl chloride S-phenylthio-Z-furoyl chloride S-c-ar-bomethoxy-2-furoyl chloride The resulting l-substituted indolyl esters are converted to the corresponding free acids by the procedure of Example 7C.

EXAMPLE L (5-chl0r0then0yl) -2-methyl-5-nieth0xy-3-ind0lyl acetic acid A. 2-METHYL-5+MET HOXY3-INDOLYLACETIC ANHYDRIDE Dicyclohexylcar bodiimide (10 g., 0.049 mole) is dissolved in a solution of Z-methyl-S-methoxy-3-indolyl-acetic acid (22 g., 0.10 mole) in 200 ml. of THF, and the solution is allowed to stand at room temperature for 2 hours. The precipitated urea is removed by filtration, and the filtrate is evaporated in vacuo to a residue and flushed with Skellysolve B. The residual oily anhydride is used without purification in the next step.

t-Butyl alcohol (25 ml.) and fused zinc chloride (0.3 g.) are added to the anhydride from part A. The solution is refluxed for 16 hours and excess alcohol is removed in vacuo. The residue is dissolved in ether, Washed several times with saturated bicarbonate, water, and saturated salt solution. After drying over magnesium sulfate, the solution is treated with charcoal, evaporated, and flushed several times with Skellysolve B for complete removal of alcohol. The residual oily ester (18 g., 93%) is used without purification.

A stirred solution of ester (18 g., 0.065 mole) in dry DMF (450 ml.) is cooled to 4 in an ice bath, and sodium hydride (4.9 g., 0.098 mole, 50% susp.) is added in portions. After minutes, S-chlorothenoyl chloride (154 g., 0.085 mole) is added dropwise during 10 minutes, and the mixture is stirred .for 9 hours without replenishing the ice bath. The mixture is then poured into 1 l. of 5% acetic acid, extracted with a mixture of ether and benzene, Washed thoroughly with Water, bicarbonate, saturated salt, dried over magnesium sulfate, treated with charcoal, and evaporated to a residue which partly crystallizes. This is shaken with ether, filtered, and the filtrate is evaporated to a residue (17 g.) which solidifies after being refrigerated overnight. The crude product is boiled with 300 ml. of Skellysolve B, cooled to room temperature, decanted from some gummy material, treated with charcoal, concentrated to 100 ml., and allowed to crystallize. The product thus obtained (10 g.) is recrystallized from 50 ml. of methanol.

A mixture of 1 g. ester and 0. 1 g. powdered porous plate is heated in an oil bath at 210 with magnetic stirring under a blanket of nitrogen for about 2 hours. No intensification of color (pale yellow) occurs during this period. After cooling under nitrogen, the product is dissolved in benzene and ether, filtered, and extracted with bicarbonate. The aqueous solution is filtered with suction to remove ether, neutralized with acetic acid, and then acidified weakly with dilute hydrochloric acid. The crude product is recrystallized from aqueous ethanol and dried in vacuo at 65.

1.2 EXAMPLE 11 1-(4,5-dichl0r0-2-then0yl) -2-methyl-5-meth0xy-3-ind0lyl a-propionic acid A. Z lHETHY-L-B METH OXY-3=I N'DOLYIr (HPR OP IONIC ANHY'DRIDE Dicyclohexylcarbodiimide (9 g., 0.044 mole) is dissolved in a solution of 2-methyl-5-methoxy-3indolyl-u-propionic acid (2 1 g., 0.09 mole) and 200 ml. of THF, and the solution is allowed to stand at room temperature for 2 hours. The precipitated urea is removed by filtration, and the filtrate is evaporated in vacuo to a residue and flushed with Skellysolve B. The residual oily anhydride is used With out purification.

B. t-BUTYL -2-METHYL-E-M'ETHOXY-3INDOLYL-a- P-ROPIONATE t-Butyl alcohol (25 ml.) and fused zinc chloride (0.3 g.) are added to the above anhydride. The solution is refluxed for 16 hours, and excess alcohol is removed in vacuo. The residue is dissolved in ether, washed several times with saturated bicarbonate, water and saturated salt solution. After drying over magnesium sulfate the solution is treated with charcoal, evaporated, and flushed several times with Skellysolve B, for complete removal of alcohol. The residual oil ester (14 g.) is used without purification.

A stirred solution of ester from part B (20 g., 0.69 mole) in 450 ml. of dry dimethylformamide is cooled to 4 in an ice bath and sodium hydride (5.2 g., 0.10 mole, 50% susp.) is added in portions. After the mixture is stirred for 10 minutes, 4,5-dichloro-2-then-oyl chloride (19.6 g., 0.091 mole) is added in portions during 10 minutes, and the mixture is stirred for 7 hours at room temperature Without replenishing the ice bath. The mixture is then poured into 1 l. of 5% acetic acid, extracted with ether, Washed thoroughly with water, bicarbonate, saturated salt solution, dried over magnesium sulfate, treated with charcoal, and evaporated in vacuo to a residue (33 g.). This is dissolved in ether, mixed with g. of acid washed alumina, and evaporated in vacuo to dryness, which is placed above a column of 300 g. of acid Washed alumina in Skellysolve B. After washing with Skellysolve B, the product is eluted with 5% ether-Skellysolve B.

D. 1- (4,5-ED LCHLORO-2-TH'ENOYL) 2-M E I HYL-5- METHOXY-B-INDOLYL-a-PROP IOiNLC ACID The pyrolysis is carried out by the procedure of xample 101). The product is recrystallized from aqueous ethanol or benzene-Skellysolve B.

EXAMPLE 12 J (5 -methoxy-2-methy l-3-then0yl) -2-methy l-5 -meth0xy- 3-ind0lyl-u-pr0pi0nic acid A. To a solution of 20.0 g. (0.07 mole) of t-butyl-rx-(Z- methyl-S- .ethoxy-3-indolyl)-propionatte in 270 ml. dimethyiformamide is added in small portions 7.0 g. (0.14 mole) of 51% sodium hydride in mineral oil under N with stirring and ice-cooling. After 15 minutes, 1.9 g. (0.10 mole) of the 5-rnethoxy-3-thenoyl chloride in 25 cc. of dimethylformamide is added dropwise, a white precipitate separates out almost immediately. The mixture is stirred at 0 for 2 hours and is allowed to stand in the cold room overnight. The next morning the mixture is filtered and diluted with ether. One-half of the solution is Washed with Water, sodium bicarbonate, water successively and dried over sodium sulfate. The dried solution is concentrated to a syrup which is chromatographed on 400 g. of acid-Washed alumina. After mineral oil and trace of impurity is eluted by petroleum ether and 5% ether in petroleum ether, the desired product is 13' obtained by elution with 10% ether in petroleum ether as yellow oil. The other half is similarly treated.

- B. The above ester and a few pieces of porousplate chips are placed in a flash submerged in an oil bath. A

steady stream of N is introduced into the test tube through M ethyl-1 (1 -methy Z-Z-carbanyl -2-methy lpyrrole- 5-methoxy-3-ind0lyl acetate A. p-NI'DROPHENYL-pCARBOBENZYLOXYALMiINO- BENZOATE 1 In a 500 mL'round bottom flask (all equipment flame dried) is added 13.9 g. of p-nitrophenol and 3.7 g. of 1-methyl-pyrrole-2-carboxylic acid in 250 ml, dry tetrahydrofuran. Through a dropping funnel is added over 30 minutes 20.6 g. of dicyclohexylcarbodiimide in 100 ml. of dry tetrahydrofuran. The reaction is allowed to run overnight with stirring. The dicyclohexylurea which forms during the reaction is filtered. The filter cake is washed with dry tetrahydrofuran. The solution is evaporated to dryness. The solid is taken up in benzene'and Washed with sodium bicarbonate solution and then with water and dried over anhydrous sodium sulfate. The solution is concentrated under vacuum to dryness. The

solid p-nitrophenyl-l-methy-l-pyrrole-2carboxylate is then recrystallized from benzene.

In a 250 ml. round bottom flask (flame dried equip-- ment) is placed at 0 C. with nitrogen, 100 ml. of dry dimethylformamide with 10.5 g. of methyl-a-(Z-methyl-S- methoxy-3-indolyl)-acetate. To this is added 2.5 g. of 50% sodium hydride mineral oil mixture. After the mixture is stirred for 30 minutes there is added over 15 minutes a solution of 4.9 g. of p-nitrophenyl-l-methyl-pyrrole- 2-carboxylate in 50, ml. dry dimethylformamide. The reaction mixture stirred for 4 hours at 0 C. under nitrogen followed by stirring under nitrogen at room temperature overnight. The reaction mixture is then poured into an ice-water-ether solution containing a few ml. of acetic acid and the layers are separated. The aqueous phase is washed with ether and the ether extracts are combined. To the ether layers is added a saturated solution of hydrogen chloride gas in dry ether. The ether is decanted off,

leaving a heavy oil. The oil is washed withjether followed by an addition of aqueous sodium bicarbonate solution. The product is then extracted with ether. The ether layer is dried over anhydrous sodium sulfate and concentrated to dryness. The product, methyl-[l-(methyl-pyrroleQ- carbonyl)-2methyl-5-methoxy-3-indolyl]-acetate, is crystallized fromdry ether.

EXAMPLE 14 Methyl(2-methyl-5-nizr0-3-ind0lyl) acetate A solution of 40 g. Of levulinic acid in 300 ml. of hot water is added to a solution of 65 g. of p-nitrophenylhydrazine hydrochloride in 700 ml. ofhot Water with stir 14 acid with stirring, and the insoluble gummy material separated is extracted with hot ethanol. The ethanolic extract is evaporated in vacuo to a syrup, which is redissolved in ether. The ether solution is extracted with 10% sodium carbonate several times. Acidificationof the aqueous solution gave a crude product which recrystallizes from chloroform to give (Z-methyl-S-nitro-Z-indolyllacetate acid,'M.P. 2380.

The above acid is treated with a mixture of 3 g. of sulfuric acid and 40 ml. of methanol at the reflux temperature for 6 hours. The methyl ester is obtained as a yellow crystalline product, M.P. 13240 after recrysstallization from benzene.

.Similarly, methyl-a-(Z-methyl-S-nitro-3-indolyl)-propionate is prepared by using an equivalent amount of a-methyl levulinic acid as the strating material.

EXAMPLE 15 M ethyl (2 -methy l-5 -amin0-3 -ind0 lyl acetate 3 g. of methyl(2-methyl-5-nitro-3-indo1yl)acetate is dissolved in 300 ml. dry methanol and reduced in hydrogen in an autoclave with Raney nickel as catalyst. After the theoretical amount of hydrogen is taken up the catalyst is removed by filtration. The catalyst and reaction flask are washed wtih methanol; The methanol solution is evaporated to dryness. The product is crystallized from benzene, M.P. 144-145".

Microanalysis.-Calc.: C, 66.03; H, 6.47; N, 12.84. Found: c, 65.96; H, 6.29; N, 12.56.

EXAMPLE l6 Methyl [2-methyl-5-(Z -pyrrolia'ino)-3-ind0lyl] acetate In a 125 ml. flask is placed 80 ml. of ethanol. To this is added 1.0 g. of methyl (Z-methyl-5-amino-3-indolyl) acetate, 0.99 g. of 1,4-dibromobutane and 0.975 g. of anhydrous sodium carbonate. This mixture is stirred at reflux temperature in a nitrogen atmosphere for 6 hours. The reaction mixture is then filtered and the filtrate is concentrated in vacuo to a small volume and diluted with ether. This solution is then Washed with water 2X dried with anhydrous sodium sulfate and concentrated in vacuo to dryness. The product is absorbed on 6 g. of silica gel. The product is then chromatographed over '30 g, of silica gel using as elutant from v./v. 3:1 ether-petroleum ether to ether. The eluted material is combined and crystallized from benzene-Skellysolve B, M.P. 117l18.

1 illicroanalysis.-Calc.: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.77; H, 7.72; N, 10.00;

When ethylene dibromide is used insetead of dibromobutane, the product obtained is the 5-(1-azacyclopropyl) indolyl compound.

EXAMPLE 17 In a dry 125 ml. flask is placed 1.2g. of methyl(2-r nethyl-5-(1-pyrrolidino)-3-indolyl) acetate in ml. of dry ring. After. about one-half hour, the hydraz one derivative is collected in a filter, washed with water and dried at110". invacuo. The yield is 84 'g. ,iM.P. 175179..

An amount of 42 g. of the above hydrazone is added to a solution of 120 g. of fused zinc chloride in 100 ml. of

absolute ethanol and the mixture is refluxed for 18 hours.

The cooled solution is poured into dilute hydrochloric dimethylformamide. To this solution, cooled to 0 C., is added 0.23 g. of 50% sodium hydride slurry in mineral oil. This mixture is stirred for 30 minutes. Then a solution of 0.8 g. of Z-thenoyl chloride diluted with Sml. of dry dimethylformamide is added dropwise. This reaction is stirred for 4 hours at 0 C. under a nitrogen atmosphere.-

The reaction mixture is then stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture is added to an ice water-ether mixture containing a few milliliters of acetic acid.

The ether layer is separated and the aqueous layer is washed with ether. The combined other layers are washed once with sodium carbonate and twice with Water, dried over anhydrous sodium sulfate and evaporated in vacuo to an oil. The product is absorbed on 10 g of silica gel and chromatographed from 60 g. silica gel. The product is collected using v./v. 1:3 to 1:1 ether-petroleum ether. The combined material is crystallized from ether.

EXAMPLE 18 M ethyl- [1 5 -chlr0-2 -fur0yl -2-metlzyl-5 -nitr0-3 indolyl] acetate In a dried 250 ml. flask is placed 3.9 g. of methyl-(2- methyl-5-nitro-3-indolyl)-acetate in 125 ml. dry dirnethylformamide. To this solution cooled to 0 C. is added 0.8 g. of 50% sodium hydride-mineral oil. This is stirred under nitrogen for 30 minutes. To this is added dropwise 2.75 g. of 5-chloro-2furoyl chloride in ml. of dry dirnethylformamide over a 5-minute period. The reaction mixture is stirred 4 hours at 0 C. under nitrogen and then stirred overnight at room temperature under nitrogen. It is then poured into an ice Water-benzene solution containing a few milliliters of acetic acid. The benzene layer is separated and the aqueous layer is washed with benzene. The combined benzene layers are washed with sodium bicarbonate followed by water, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The product is crystallized from benzene-Skellysolve B.

The corresponding propionate is formed when an equivalent amount of the corresponding methyl-a-(Z-methyI-S- nitro-3-indolyl) propionate prepared in Example 4 is used as the starting material.

EXAMPLE 19 M ethyl- [1 (5 -ch loro-Z -fur0yl -2 -methyl-5 -a' imethylamin0-3-ind0lyl] acetate To a solution of 0.387 g. of methyl-CMl-(5-chloro-2- furoyl)-2-methyl-5-nitro-3-indolyl] acetate in 20 ml. of distilled dirnethoxyethane is added 1.5 ml. of glacial acetic acid and 0.5 ml. of a 37% solution of aqueous formaldehyde. This mixture is reduced with Raney nickel at 40 p.s.i. and room temperature. After the theoretical amount of hydrogen has reacted, the reaction mixture is filtered, concentrated in vacuo to a small volume and diluted with ether. The ether solution is washed with sodium bicarbonate, then with water, dried with anhydrous sodium sulfate and concentrated in vacuo.

EXAMPLE 20 Methyl- [1-(5-chl0r0-2-fur0yl) -2-methyl-5-acezamin0- 3-ind0lyl] acetate To 0.388 g. of methyl-[1-(5-chloro-2-furoyl)-2-metl1yl- S-nitro-S-indolyl] acetate in 30 ml. of anhydrous ethyl acetate is added 0.306 g. acetic anhydride. The mixture is reduced with Raney nickel at room temperature and 40 p.s.i. After the theoretical amount of hydrogen has been absorbed, the catalyst is removed by filtration. The solution is concentrated in vacuo to a small volume and poured into an ice-water-ether mixture. The ether layer is separated and the aqueous layer is washed with ether. The combined ether extracts are washed with sodium bicarbonate followed by water, dried with anhydrous sodium sulfate and concentrated in vacuo to dryness. The product is crystallized from benzene and ether.

EXAMPLE 21 Benzyl- 2-methyl-5-nitr0-3-ind0lyl) acetate In a dry 250 ml. flask is placed 80 ml. dry benzene and 20 ml. benzyl alcohol. To this is added 3.0 g. of Z-methyl- 5-nitro-3-indolyl acetic acid and 0.2 g. of p-toluene sulfonic acid. This slurry (which clears on heating) is heated to reflux under nitrogen. The water formed during the reaction is collected in a Stark and Dean tube. The reaction is stopped when the distillate is clear (about 2 hours). The excess benzyl alcohol is removed in vacuo. The residue is dissolved in benzene and washed with sodium bicarbonate followed by water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The product is absorbed on 15 g. of acid-washed alumina and chromatographed over 75 g. of acid-washed alumina.

The 5 16 product is eluted with v./v. 111-311 etherbenzene. The eluate is evaporated and the combined product is crystallized from benzene-Skellysolve B. MP. 147-148. Micr0analysis.-Calc.: C, 66.66; H, 4.97; N, 8.64. Found: C, 66.83;?1, 4.77; N, 8.52.

EXAMPLE 22 Benzyl- [1 5 -chl0ro-2 Juroyl -2-m ethyl-5 -11z'tr0-3 indolyl] acetate In a dry 25 ml. flask is placed 3.0 g. of benzyl-(Z-methyl5nitro-3-indolyl) acetate in 60 ml. of dry dimethylformamide. To this solution, cooled to 0 C. in a nitrogen atmosphere is added 0.475 g. of 50% sodium hydridemineral oil. This is stirred for minutes. Then 1.65 g. of 5-chloro-2-furoyl chloride in 10 ml. of dry dirnethylformamide is added dropwise over a 5-minute period. The reaction mixture is stirred at 0 C. for 4 hours under a nitrogen atmosphere followed by stirring at room temperature under nitrogen overnight. It is then poured into an ice water-benzene mixture. The benzene layer is separated and the aqueous layer is washed with benzene. The combined benzene extracts are washed with sodium bicarbonate followed by water, dried with anhydrous sodium sulfate and concentrated in vacuo to dryness. The product is crystallized from benzene-Skellysolve B.

EXAMPLE 23 1V! etiz yl-a- I (5 -chl0ro-2-furoyl) -2 -meth yl-5 -amin0-3 indolyl] -pr0pi0nate 0.025 M of methyl-0H1-(5-chloro-2-furoyl)-2-methyl- 5-nitro-3-indolyl] propionate in 100 ml. of ethanol is hydrogenated in the presence of 120 mg. of 10% palladium EXAMPLE 24 Iv! ethyl-1 -p-chl0r0benz0yl-2-methy l-5-methylamino-3- indolylacetone A mixture of 1.1 mole of carbobenzyloxy chloride 500 ml. of pyridine and 1.0 mole of methyl-[l-(S-chloro-Z- furoyl)-2-methyl-5-amino-3-indolyl]-acetate is stirred at room temperature four hours. It is then poured into water and the 5-carbobenzyloxyamino indolyl compound is filtered, Washed and dried.

The S-carbobenzyloxyamino indolyl compound is then added to a suspension of sodium hydride in dimethylformamide with stirring and ice-cooling. After one hour, methyliodide is added and the mixture is stirred overnight. The reaction mixture is poured into ice water and extracted with ether. Evaporation of the ethereal solution and chromatography of the residual oil on an alumina column, using 15-25% (v./v.) ether in petroleum ether as the eluent, gives methyl-[1-(5-chloro-2-furoyl)- 2-methyl-5-(N methyl carbobcnzyloxyamino)-3 indolyIJ-acetate.

The product is subjected to hydrogenation at atmospheric pressure over palladium on charcoal, in ether solution. The mixture is then filtered to remove the catalyst. Evaporation of the ether gives methyl-[l-(S-chloro-Z- furoyl-2-methyl-5-methylamino-3-indoyl]-acetate.

EXAMPLE 25 A mixture of 0.02 mole of methyl-a-[l-(S-chloro-Z- furoyl) 2-methyl-5-amino 3 indolyl)propionate, 0.044 mole of ethylene oxide and 0.03 mole of acetic acid in 300 ml. dimethoxyethane is heated to for 18 hours in an autoclave. The mixture is then diluted with Water and filtered to yeld crude methyl-[1-(5-chloro-2furoyl)-2 The product of A is stirred at in pyridine with two mole proportions of p-toleuenesulfonyl chloride until the reaction is substantially complete.

The mixture is poured.

into water and the S-bis(p-toluenesulfonyl-oxyethyl) amino compounds is isolated. This is dissolved in benzene and one mole proportion of methylamine is added. The mixture is allowed to stand at room temperature for 3 days. The mixture is poured into iced water containing two equivalents of sodium carbonate and extracted with ether immediately. Evaporation of the ether yields methyl-[1- (5-chloro-2-furoyl) 2-methyl-5-(4-methyl-l'-piperazin yl)-3-indolyl] acetate.

Either of the above products, that form Part A or Part B, when used in the procedure of Example 7, gives the corresponding free acid.

EXAMPLE 26 M ethyl- [I (5 -chZ0r0-2-fur0yl -2-methyl -5 (4T- morpholinyl) -3-ind0lyl] acetate A solution of tosyl chloride (0.1 mole) in 200 ml. ben zene is added dropwise with stirring to a solutionof methyl-u-[l-p chlorobenzoyl-2-methyl-5-bis('fl-hydroxyethyl) amino-3-indolyl]acetate (0.1 mole) and pyridine (0.3 mole) in 300 ml. benzene at room temperature over a period of one hour. The mixture is then heatedunder reflux for 3 hours, washed with water, dried over sodium sulfate and evaporated to a syrup. Chromatography of the syrup on an alumina column using 30-50% (v./v.) ether in petroleum ether as the eluentgives methyl-[l-(S- chloro-Z-furoyl) Z-methyl-S-(4'-morpholinyl) 3 indolyIJacetate. r

The above product, when used in the procedure of Example 7, gives the corresponding free acid.

EXAMPLE 27 A solution of p-cyano phenylhydrazine (0.1 mole) and levulinic acid (0.1 mole) in 200 ml. concentrated hydrochloric acid is heated at 90 for minutes andidiluted The S-cyano ester prepared inExample 27B is hydrogenated in ethanol in the presence of Raney nickel and 1 3 moles of anhydrous ammoniaat ZOOO p.s.i-. at room temperature to give, after filtrationof the catalyst and evaporation of the reaction mixture, methyl [l-( S-chloro- 2-furoyl)-2-methyl-5-aminomethyl 3 indolyl] acetate which can be recrystallized from aqueous ethanol.

Treatment of the above .oa-fiHIlHOIIlCthYl indole with 2 moles of methyl iodide gives the S-dimethylamino-methyl derivative. When ethyl iodide is used in place of methyl iodide, the S-diethylaminomethyl derivative is obtained.

- 1. When the products of Examples 27C and 27D above are used in the procedure of'Example 7, the corresponding free acids are obtained.

EXAMPLE 28 ,oc- (1 -thenoyl-2-methy l-5-meth0xy-3-indolyl -butyric acid When the procedure of Examples 1 and 2 are followed using ethyl a-ethyl levulinate in place of ethyl a-methyl levulinate, there is obtained successively ethyl a-(2- methyl-5-methoxy-3-indolyl)-butyrate and ethyl a-(lthenoyl-2-methyl-5-methoxy-3-indolyl) butyrate. When the latter product is used in the procedure of Example 7 the corresponding butyric acid derivative is obtained.

The starting ethyl a-ethyl levulinate is prepared by alkylation of the sodio derivative of ethyl acetoacetate in ethanol with 1 m. of ethyl u-bromobutyrate, followed with iced water (400 ml.). The crude productwhich by hydrolysis and decarboxylation. The u-ethyl levulinic acid obtained is reesterified with 2 N ethanolic hydrogen chloride at reflux temperature for 18 hours.

EXAMPLE 29 of Water is added with vigorous stirring. The mixture is stirred until it is homogeneous and the solid aluminum salt of (1-thenoyl-2-methyl-5-metl1oxy-3-indolyl) acetic acid, is recovered by filtration and-washed with water and with ethanol.

In a similar fashion, there may beprepared the sodium and aluminum salts as well as other salts, such as the potassium, and magnesium salts, of the various (3- indolyl) aliphatic acids described in the accompanying I examples.

EXAMPLE vso S-chlorothenoyI-Z-meihyIrS-meth0xy-3-ind0lyl v acetic anhydride EXAMPLE 31 T he corresponding N -l aroyl or heteroaroyl derivatives of benzyl-a-(2-methyl-5-methoxy-3-indo1yl) propionate, benzyl (2methyl-S-methoxy-B-indolyl) acetate and benzyl- (2-niethyl-5-nitro-3-indolyl)acetate are obtained by reacting these esters by the. procedure of Example 133 with the p-nitrophenylesters of the following acids, the p-nitro- I phenyl esters having been obtained from the acids by the procedure of Example '1 3A, using in each case the equiv alent amount of the selected acid in place of the 1 rnethylpyrrole-2-carboxylic acid used in 13A andof its nitro phenyl esters used in 1313 and equivalent quantities of the indolyl esters: a

2-(2-pyridyl)-3-furoic acid -4-methoxy-1-methyl-pyrrole-2ecarboxylic acid 1:phenyl-3-cyanopyrrole-2-carboxylic acid 1-ally1-3- cyanopyrrole-2-carboxylic acid 1-benzyl-3-cyanopyrrole-2-carboxylic acid 1-cyc1ohexyl-3-cyanopyrrole-Z-carboxylic acid l-phenylpyrrole-3-carboxylic acid 1-benzyl-Z-methyl-5-formylpyrrole-3-carboxylic acid S-benzoyl-l,2,4-trimethylpyrrole-3-carboxylic acid 1,2-dimethyl-4-isopropylpyrrole-3-carboxylic acid 1-methyl-3-benzyloxy-4-isopropylpyrrole-Z-carboxylic acid 1-butyl-4-nitropyrrole-2-carboxylic acid 1 ,3 -dimethy1-4-ethyl-5-ethoxymethylpyrrole-2-ca rb oxylic acid 4-chloro-l,3,S-trimethylpyrrole-Z-carboxylic acid 1-methyl-4-nitropyrrole-2-carboxylic acid 2,5-dibrorno-1,4-dimethylpyrrole-3-carboxylic acid .l-methyl-S-formylpyrrole-2-carboxylic acid 1,2,4-trimethylpyrrole-3-carboxylic acid S-acetyl-1,2,4-trimethylpyrrole-3-carboxylic acid 4-cyanomethyl-1,3,5-trimethylpyrrolc-2-carboxylic acid The esters so obtained are converted to the free acids by the procedure of Example 7C.

EXAMPLE 32 E thy l-a- [I (5 -chlr0-2- ur0yl-2 -methy l- -eth0xy- 3-indolyl] propionate The procedure of Example 1A is followed using an equivalent quantity of p-ethoxyphenylhydrazine hydrochloride in place of the methoxyphenylhydrazine to give thy1-Ot-( 2-methyl-5-ethoxy 3-indolyl)propionate. When this is used in the Procedure of Example 3, there is obtained GlhYl-a-[l-(S-ChlOIO 2 furoyl)-2-methyl-5-methoxy-3-indolyl) propionate. This product, when used in the procedure of Example 7, yields the corresponding free a-indolyl propionic acid.

Similarly, when p-propoxy, p-butoxy, p-benzyloxy, p-4- methyl'benzyloxy, p-4-methoxybenzyloxy, p-4-chlorobenzyloxy phenylhydrazine are used in the above procedures, the correspondingly S-substituted indolyl acids are obtained. When the '1-(5-chloro-2-furoyl)-2-rnethyl-5-benzyloxy- (or substituted benzyloxy)-3-indolyl propionic acids so prepared are subjected to catalytic hydrogenation over palladium, there is obtained oc-[l-(S-CillOIO-Z-fllroyl -2-methyl-5-hydroxy-3-indolyl] propionic acid.

When the procedure of Example 1A is followed using in place of the p-methoxyphenylhydrazine, equivalent amounts of p-ethylphenylhydrazine, p-butylphenylhydrazine, p-trifiuoromethylphenylhydrazine, p-chloro-phenylhydrazine and p-fluorophenylhydrazine (each obtainable by diazotization of the corresponding p-substituted aniline and reduction of the diazo) and the resultant indolyl ester is acylated by the procedure of Example 3 and further treated by the procedure of Example 7, the corresponding S-substituted indolyl esters and acids are obtained.

When the procedure of Examples 1A, 3 and 7 are followed starting with phenylhydrazine, the corresponding 5- unsubstituted indolyl esters and acid are produced.

EXAMPLE 33 I-then0yl-2-metlzyl-5-meth0xy-3-ind0lyl-acetamide EXAMPLE 34 1-tlzenoyl-2-methyl-5-metlz0xy-3-ind0lyl-acetic acid To a solution of 3.2 g. of 1-thenoyl-2-methyl-5-methoxy-3-indolylacetamide in 50 ml. dimethoxyethane containing 1 ml. of 12 N hydrochloric acid at 0 is added 0.7 g. of sodium nitrite with stirring. After gas evolution has Z-thenoate.

subsided the mixture is poured into 200 ml. of iced Water and the precipitate is extracted with methylene chloride. The methylene chloride solution is extracted with sodium bicarbonate solution. Acidification of the aqueous solution with 2 N hydrochloric acid precipitates the desired acid which is purified by recrystallization from benzene and from ethyl acetate-Skellysolve B.

EXAMPLE 35 A. '5 DIMETHYLCA RB AMIDO-QJHEN01C ACID A solution of 0.02 mole of S-carbomethoxy-Z-thenoyl chloride (prepared by heating the free acid with thionyl chloride) in ether is added with stirring and ice cooling to a solution of excess dimethylamino in ether. The mixture is then washed with water followed by dilute HCl and water again. After it is dried over sodium sulfate, the solution is evaporated to give methyl S-dimethylamino-2-thenoate. This product (0.02 mole) is stirred with 40 ml. of N NaOH in aqueous ethanol at room temperature for 18 hours. The mixture is then concentrated to /5 volume in vacuo, poured into water and extracted with ether. The aqueous solution is then acidified to give 5-dimethylcarbamido-2-thenoic acid.

When the dimethyl amine is replaced with diethylamine, methyl propyl amine, or dibutylamine, the corresponding amidothenoic acids are obtained.

B. 5- l-MORPHODINO )CARBONYL-Z-THENOIC ACID The procedure of Part A is followed using an equivalent quantity of morpholine or pyrrolidine in place of the dimethylamine, to give respectively 5-(4-morpholine)carbonyl-Z-thenoic acid and 5(l-pyrrolidinyl)carbonyl-2- thenoic acid.

.C. 5-DIMETHYLC-ARBAMIDO-JZ-FU'ROIC ACID The procedure of part A is followed using S-carbomethoxy-Z-furoyl chloride (prepared by heating the free acid with thionyl chloride) in place of the coresponding thenoyl chloride, to give S-dimethyl carbamido-Z-furoic acid. When the dimethylamine is also replaced with diethylarnine, methyl propylamine, dibutylamino, morpholine or pyrrolidine, there is obtained S-diethylcarbamido, S-methylpropylcarbamido, S-dibutylcarbamido, 5-(4-morpho1ino) carbonyl or 5-(1-pyrrolidinyl)carbonyl Z-furoic acid respectively.

A solution of 0.02 mole of S-chlorosulfonyl-Z-furoic acid in 40 ml. of 1,2-dimetl1oxyethane is added to a cold solution of 0.06 mole of dimethylamine in 200 ml. of 1,2-dimethoxyethane. The mixture is stirred and kept at 0-5 C. for 4 hours and then at ambient temperature for 18 hours. It is then concentrated in vacuo to A volume and poured into ice and water. After acidification with dilute HCl, the mixture is extracted with ether, the extract dried over Na SO and evaporated to yield S-dimethylsulfamyl-Z-furoic acid.

When the dimethylamine in the above procedure is replaced with diethylamino, methylpropylamine, dibutylamino, morpholine or pyrrolidine, the corresponding 5- dialkylsulfamyl-Z-furoic acids are obtained.

E. 5-FLUOROMETHYL-2-THENOIC lA C'ID A olution of 0.05 mole of methyl S-chloromethylthiophcne-Z-carboxylate in toluene is heated under reflux with 0.1 mole of silver fluoride for 18 hours. After filtration, the mixture is chromatographed on a column of 300 g. acid-washed alumina, using ether-petroleum ether (v./v.) 10-50% .as eluent to give methyl S-fluorornethyl- Hydrolysis of the above ether with 1 N sodium hydroxide in 90% aqueous alcohol at room tem pergture for 18 hours gives S-fiuoromethyl-Z-thenoic aci When in the above procedure, the 5-chloromethyl-2- thenoic acid is replaced by S-chloromethyl-Z-furoic acid, there is obtained S-fiuoromethyl-Z-furoic acid.

I". S-DIFLUOROME'IIIYL-2-THENOIC ACID A solution of 0.05 mole of methyl 5-formyl-2-thenoale in benzene is treated with 0.1 mole of phosphorous pentachloride at room temperature for 1 hour and then at the reflux temperature for 2 hours. The solution is poured into crushed ice. The organic layer is washed with saturated HaHCO water and dried over Na,SO The solution is evaporated in vacuo to a syrup and the crude methyl S-dichloromethyl-Z-thenoate is redissolved in toluone and heated at the reflux temperature with 0.2 mole of silver fluoride for 24 hours. After filtration, the solution is concentrated in vacuo and chromatographed on 400 g. of acid-washed alumina to yield methyl S-ditluoromethyl-2-thenoate. Hydrolysis of the ester with N NaOH in 80% aqueous ethanol at room temperature for 18 hours gives S-dilluoromethyl-Z-thenoic acid.

The same compounds are obtained by an alternative procedure:

A mixture of 0.05 mole of methyl S-t'ormyl-Z-thenoate, 0.05 mi. of water and 0.2 mole of SF. is heated in an autoclave at l20-l50 C. for 8-12 hours. The mixture is poured into crushed ice and extracted withether. The ether solution is washed with saturated NaHCO,, 11,0 and dried over Na,SO.. After evaporation, the crude mixture is chromatographed on a column of 300 g. of acid-washed alumina, using ether-petroleum ether (v./v.) tO-SOZ: as eluent to give methyl S-ditiuoromethyl-Z-thcnoate which is saponilied as before.

When the above procedure is followed using methyl- 5-formyl-2-fluorate in place of the methyl formylthenoate, there is obtained 5ditiuoromethyl-2-t'uroic acid.

0. B-TillFLUOi'lOhlI-JTIIYLd-THENOIC ACID The second or alternative procedure in part F is followed using S-carbomethoxy-Z-thenoie acid in place of the methyl S-formyl-Z-thcnoate. The product methyl-$- tritluoromethyi-Z-thenoate is hydrolyzed, as in that procedure, with N NaOli in aqueous ethanol, to give S-tritluoromcthyl-2-thenoic acid.

when S-carbomcthxy-2-furoic acid is used in the above procedure there is similarly obtained -tritiuoromcthyl-Z-turoic acid.

EXAMPLE as The acyiation procedure of Example 12A is followed using the acid chlorides of the various acids prepared in Exam le 35 (obtained by heating the acid with thionyl chloride) in equivalent quantities in place of S-methoxy- 2-mcthyl-3-thenoyl chloride and using. as necessary, eaten 0t 2-mcthyi-S-mcthoxy-J-indolyi acetic acid or of alpha- (2-methyl-S-mcthoxy-S-indolyi) propionic acid. Some of 22 methyi-[ l-(S-triliuoromethyl-2-thenoyl)-2- methyl-S-mcthoxy-li-indolyl]acetate, and methyl-[ i-(S-triiiuoromethyl-Z-furoyl-Z- methyl-S-methoxy-3-indolyl acetate.

EXAMPLE 37 EXAMPLE 38 MethyH-(S-cldoro-Z-Iuroyl) -2-methyl-5-allyloxy- 3-tnd0lyl acetate A. METHYL BJIYDROXY-fl-METHYLQ-INDOLYL ACETATE A mixture of 10 g. of methyl S-methoxy-2-methyi-3- indoiyl-acetate and g. of pyridine hydrochloride is heated at 180 under nitrogen for 15 minutes. The reaction mixture is then cooled to about $0, dissolved in 150 mi. of 1.5 N methanolie hydrogen chloride and refiuxed for 2 hours. After cooling. the solution is concentrated in vacuo, poured into water and extracted with ether. The ethereal solution is washed with water and extracted three times with 50 ml. of 5% sodium hydroxide. The combined aqueous extract is acidified to pH 6 and extracted with ether. After drying over sodium sulfate, the ethereal solution is evaporated to give methyl- S-hydroxy-Z-methyi-S-lndolyl acetate, recrystallized from benzene, MP. 158-170 (3.4 g.).

B. armnm-sm'mtm-aannexes-moons. Jtcmwm A mixture of 3.4 g. of the S-hydroxyindoie, 2.4 g. of allylbromide and 7.5 g. of potassium carbonate is stirred at room temperature to 56' for 18 to 6 hours. The reaction mixture is filtered, concentrated in vacuo to a syrup and chromatographed on 60 g. of silica gel, using vJv. 50% ether in petroleum ether as eluent to give 0.7 ghol methyl S-aliyioxy-Z-methyl-S-indolyl acetate as an o C. [-(B-CHIDRO-2 FUROYL)-2-hlF2'll'lYM-ALLYIDXY-3- INDOLYL ACETATE The procedure of Example 3 is followed, using the above S-aiiyloxy compound in place of the S-methoxy compound to give methyl [i (S chloro-2-iuroyi)-2- methyl-5-allyloxy-3-indoiyl] acetate.

Similarly when allyi bromide is replaced by an equivalent amount of cyciopropylmcthyl bromide, cyclobutylmethyl bromide, and isopropyl bromide, the corresponding 5 cyciopropyimethoxy 5 cyciobutylmethoxy, isopropoxyanalogs are obtained.

EXAMPLE 39 .i-trifluoromethyiphcnylhydrazine 2S0 mis. of chilled concentrated hydrochloric acid is slowly added with stirring, to 0.40 of a mole of fneshly distilled B-aminobenzotrifluoride, which is kept cooled in an ice salt bath. When the temperature of the above suspension is 0, a precooled solution of 0.40 of a mole of sodium nitrite in 125 mis. of water is added through a separating funnel, whose tip is immersed below the surface of the suspension. The addition is carried out over minutes, maintaining the reaction below 3'. A chilled solution of 0.89 mole of stannous chloride dihydrate'in 200 mis. of concentrated hydrochloric acid is then added dropwise to this stirred and cooled diazonium solution, over a period of three hours. During this addition, the temperature is maintained at 0-5' and after the addition, the solution is stirred for an additional hour at The resulting solid is collected by filtration, pressed as dry as possible and then shaken with 700 mls. of 25% sodium hydroxide. The yellow mixture obtained is allowed to stand overnight at room temperature. The mixture is then extracted with three 300 ml. portions of benzene. The combined filtered benzene solution is dried over 20-30 gms. of potassium hydroxide. Distillation, under vacuum, of this benzene solution gives 3-triiluoro methylphenylhydrazine.

When equivalent amounts of 2-aminobenzotrilluoride, 4-mcthoxy-3-tritluoromethylaniline, 4-methoxy-2-triiluoromethylaniline. 4-nitro-3-tril'luoromethylaniline, 4-nitro-2- trilluoromethylanilinc. or 4-methyl-3-trit'luoromethylaniline is employed in the above procedure in place of 3- nminohcnzotrilluoridc, there is obtained 2-trifluoromcthylphenylhydrazine, 4 methoxy 3 trilluoromethylphenylhydrazine. 4-methoxy-Z-trilluoromcthylhydrazine, 4-nitro- 3 trillunromethylphcnylhydrazine. 4 nitro-Z-tritluoromethylphenylhydrazine. or 4 methyl-3-tritluoromethylphenylhydrazine, respectively.

EXAMPLE 40 r\lerlr vl-4 and 6-rri iuorometliyl-3-lndolyiacetarc 0.2 mole of methyl-wy-dimethoxybutyrate is added.

dropwise with stirring, to a solution of 0.2 mole of J-trilluoromethylphcnylhydraziae in 75 ml. of 50% acetic acid. The mixture is allowed to stir at room temperature for three hours, and then 300 ml. of water is added. The crude hydrazone which separates out is collected and dried in vacuo. 0.04 mole of the dried hydrazone is then intimately mixed with 0.85 mole of freshly fused zinc chloride. To this mixture is added, with stirring. for 5 minutes at room temperature, 135 ml. of glacial acetic acid and 5 ml. acetic anhydride. The mixture is then refluxed for one hour and cooled to room temperature. This resulting mixture is poured onto chopped ice and water and allowed to stand overnight in a refrigerator. The solid is collected and precipitated by filtration and chromatographed on acid-washed alumina and eluted with ether-petroleum ether (v./v. 5-5096). The two isomers which are obtained, namely, methyl-(4-trilluoromethyl-3-indolyl)acetate and methyl-(6-trilluoromethyl- 3-indoiyl)acetate are differentiated by nuclear magnetic resonance spectroscopy.

When equivalent amounts of 4-methoxy-3-trilluoromethylphenylhydrazine. 4 nitro 3 trilluoromcthylphenylhydrazine, or 4'mcthyl 3 trilluoromcthylphenylhydrazine is employed in the above procedure in place of B-trltiuoromethylphenylhydrazine, there is obtained both isomers of each, namely methyl-t5-methoxy4trit'luoromethylJ-indolynacctate, methyl-(S-methoxy-Mrilluoromethyl-J-indolyl) acetate; methyl-(S-nitroA-tritluorm methyl 3 iadolyUaeetate: methyl-($-nitro6-tritluoromethyl 3 indolyl)acetate; or methyl (S methyM-trltluoromethyl 3 indoiyl)acetate; methyl-(S-methyl-G-triliuoromethyl-S-lndolyl)acetate, respectively.

Similary, when equivalent amounts of Z-tritluoromethylphenylhydrazine, 4-methoxy-2-tritluoromethylhydrazine, 4-nitro-2-triliuoromethylphenylhydrazine, or 4-methyl-2- triiluoromcthylphenyihydrazine is employed in place of 3 trllluoromethylphenylhydrazine, there is obtained methyl (7 tritluoromethyl-J-indolyl)acctatc; methyl- (5 methoxy 7 trilluoromethyl 3 indolyl)acetate; methyl-(S-nitroJ-trilluoromethyl 3 indolyl)acetate, or methyl-(S-methyl-7-tritluoromethyl-S-indolyl)acetate, re spectlvely.

EXAMPLE 4! Methyl-e44 or 6-rrl/iuor0merhylJ-lndolyl]pr plonare When the procedure of Example 40 is followed, using methyl-wy-dlmethoay a methyl butyrate in place of methyl-wrdlmethoxybutyrate, there are obtained two isomers, namely, methyl-a-(4-trllluoromethyl-3-indolyl) propionate and methyl a (6-trilluoromcthyl-S-indolyl) propionate.

When equivalent amounts of 4methoxy-3-tritluoromcthylphenylhydrazine, 4-nitro-3-trifiuoromethylphenylhydrazine, or 4-methyl-3-trilluororiiethylphenylhydrazine is employed in place of S-trifluoromethylphenyihydrazine, there are obtained both isomers of each, namely, mcthyla-(5-methoxy-4-trilluoromethyl 3 indolyl)propionate, methyl a (S-methoxy-G-trilluoromethyl-3-indolyl)pro pionate,; methyl a (S-nitro-4-trifluoromethyl-Z-indolyl)- propionate, methyl a (5 nitro-G-tritluoromethyl-B-indolyl)-propionate, methyl-a-(5-methyl-6-trifluoromethyl 3-indolyl)-propionate, respectively.

Similarly, when equivalent amounts of 2-trilluoromethylphenylhydrazine, 4 methoxy 2 trilluoromethylphcnylhydrazine, 4-nitro-2-trilluoromcthylphenylhydrazine, or 4- mcthyl-Z-trifluoromethylphenylhydrazine is employed in place of B-trifiuoromethylphcnylhydrazine, there is obtained mcthyl-a-(7-trillu0romethyl-3-indolyl)propionate, methyl a (S-methoxy-7-tritluoromethyl-J-indolyl)-propionate, methyl a- (S-nitro-7-trifluoromcthyl-3-indoiyl) propionate, or methyl-w(S-methyl-7-trllluorOmethyl-B-in dolyl)propionate, respectively.

EXAMPLE 42 Merhyi-(2-merhyl-4 or 6-rrifluoromethyi-3- indolyhacerare When the procedure ot Example 40 igfollowcd, using methyl ievulinate in place of methyl-yn-dimethoxybatyrate, there is obtained two isomers, namely, methyl-(2- methyM-tritluoromethyl-B-lndoiyl)acetate and methyl- (Z-methyl-6-trilluoromethyl-Il-indoiyl)aeetate.

When equivalent amounts of 4-methoxy-3-tritluoromethylphenylhydrazine, 4 nitro-J-trifluoromethylphenylhydrazine, or 4 methyl 3 trilluoromethylphenylhydrazine is employed in place of B-trilluoromethylphenylhydrazine, there is obtained both isomers of each, namely. methyl-(S-methoxy-2-methyl 4 trilluoromethyl 3 in doiyl)acctate, methyl (5 meth0xy-2-mcthyl-6-triiluoromethyl-J-indolyl)acetate; methyl-(2-methyl-5-nitro-4-trit'luoromethyl-B-indolyl)acetate, methyl-(Z-methyl-S-nitro- 6 trilluoromethyl 3 lndoiyi)acetate; or methyl-(2,5- dimcthyl-4-trilluoromethyl-3-lndolyl)-acetate, methyl-(2,5- dimethyM-tritluoromethyi-J-indolyl)acetate, respectively.

Similary. when equivalent amounts of Z-trilluoromethyl phenylhydrazine, 4 methoxy 2 trilluoromethylphenylhydrazine, 4-nitro-2-trilluoromethylphenylhydrazine, or 4-methyl-2-triliuoromethylphenylhydrazine is employed in place of 3-trllluoromethylpheayihydrazine, there is ob tained methyl (2 methyl-7-tritluoromcthyl-J-indolyi)- aeetate, methyl-($-methoxy-2-methyi-7-trilluoromethyl-S- indolyl) acetate, methyl (Z-methyl-S-nitro-7-trifluoromethyl-S-indolyl)-acetate. 0r methyl-(2,5-dimethyl-7-tri tluoromcthyl-B-indolyl)-acetate, respectively.

EXAMPLE 43 Merhyl-e- (2-metlryl-rrifiuoromerhyl-JJndoiy-l propionare When the procedure of Example 40 is followed, using propionate, methyl-a-(2,5-dimethyl 6 trilluoromethyl-3- indolyl)propionate, respectively.

Similarly, when equivalent quantities of 2-trifluoromethylphenylhydrazine, 4-methoxy 2 triiluoromethylphenylhydrazine, 4-nitro-2 triiiuoromethylphenylhydrazinc, or 4-methyl-2-trilluoromethylphenylhydmzine is employed in place of 3-tril'luoromethylphenylhydrazine, there is obtained methyl-a-(Z-methyl-7-trifluoromethyl-3- indolyl)-propionate, methyl-a -(fi-methoxy 2 methyl-7- trilluoromethyl-Zi-indolyl)-propionate, methyI-e-(Z-methyl-S-nitro7-trilluoromethyl 3 indolyl)-propionate, or

\methyl-e-(25dimethyl-7-triiiuoromethyl-3 indolyl)-propionate, respectively.

EXAMPLE 44 (l -/uro -i-4-trifluorometItyl-3-indoiyl)acetic acid A. A solution of 0.05 mole of methyl-(4-trilluoromethyl-3-indolyl)acetate and 0.01

mole of sodium in 60 ml. anhydrous bcnzyl alcohol is slowly fractionated over a period of 4% hours through a Vigreux column to remove methanol. The excess bcnzyl alcohol is removed by distillation at 60' and 2.5 mm. to give a residue of crude benzyl-(+tritluoromethyl-3-indo1yl)acctate.

B. A suspension of 0.046 mole of 50% sodium hydride-mineral oil in 250 ml. of dimcthylt'ormamide is stirred for 20 minutes under nitrogen, with ice-cooling. Then 0.035 mole of the bcnzyl ester obtained above is added and the mixture stirred for 20 minutes. 0.046 mole of turoylchloride in 50 ml. of dimethylforrnamide is addcd dropwise over a period of 30 minutes. The mixture is stirred in an ice-bath for 5 hours under nitrogen, then poured into a mixture of 500 ml. of ether, 5 ml. of

acetic acid and 1.1 ml. of iced water. The organic products are extracted with 3 x 300 ml. of ether. The

ether solutions are combined and washed with a large quantity of water, and dried over sodium sulfate. The solution is filtered, evaporated to near dryness and the residue charged onto a 300 g. alutnina column. The

benzyl-( l-furoyl-4-trifiuoromethyl 3 indolyl)acetate is eluted with ether-petroleum ether (540% v./v.).

0.02 mole of the ester obtained in part B is added to l 50 ml. of ethyl acetate containing a drop of acetic acid and is reduced catalytlcally at room temperature in the presence of palladium on plction of the reduction,

charcoal catalyst. Upon comthe catalyst is removed by-filtration and the filtrate evaporated to yield t-furoyl-Mrifiuoromethyl-Z-indolyl acetic acid.

When the methyl esters described in Examples 41, 42, 43, and 44 are used in the above procedures, the corresponding l-benzoyl-i-lndolyl acetic or 3-indolyl-e-propionic acid derivatives are obtained.

when, in the above procedure, S-chloro-Z-furoylchloride, 5-rnethylthio-Z-furoylchloride,

S-methoxy-Z-thendyh chloride. or S-benzyloxybenzoyl chloride are used in place of the furoyichloride, the corresponding l-acyl-S- indolyl acids are obtained.

EXAMPLE 45 I -luroyi-5-dlmelhyiamlno-4-tri/lu0romethyi-d-indoiyi acetle acid distilled dimcthoxyethane. This mixture and room temperature.

Rancy nickel at 40 p.s.i.

is reduced with After the theoretical amount of hydrogen has been taken up. the reaction mixture is filtered. The catalyst is washed well with ether. The combined filtrate. and ether washings are washed and evaporated in vacuo to yield with water, dried over sodium sulfateaminc-Mrilluoromethyl-J-indolyl)acetic acid.

when the l-acyl-Smltro-S-lndolyl acid compounds in Example 44 are used in equivalent quantities in place of l-furoyl4-trilluoromethyl-S-nltro-3-indolyl acetic acid, in

the above procedure, l-acyl-S-dimethylamino derivatives.

there are obtained the corresponding 2G EXAMPLE 46 EXAMPLE 47 PropyH l -thenoyi-4-trifluoromethyi-3-irrdolyi acetate A solution of 0.0054 mole of N,N'-dicyclohexylcarbodiimido in 60 ml. of anhydrous tetrahydrofuran is added to a solution of 0.005 mole of l-thenoyl-4-trilluoro methyl-Ii-indolyl acetic acid and 0.0054 mole of n-propyl alcohol in 25 ml. of anhydrous tetrahydrot'uran. The reaction mixture is shaken vigorously and allowed to stand at room temperature overnight. The dicyclohexyl urea is filtered oli and 2 ml. of glacial acetic acid is added to the filtrate. The mixture is allowed to stand for one hour. The solution is filtered and about 200 ml. of ether is added to the filtrate. This filtrate is then extracted well with water. The ether solution is dried over sodium sulfate and concentrated in vacuo. The crude material is chromatographed on alumina using etherpetroleum ether (v./v. 5-5096 to obtain propyl l-thenoyl- 4-trifiuoromethyl-3-indoly1 acetate.

EXAMPLE 4:; 2-fluoro-4-metlrylphenylhydrazine 150 ml. of concentrated HCl is slowly added with stirring to 0.1 mole of 2-fluoro-4-methylaniline. When the temperature of this suspension is at l', 0.1 mole of 40% sodium nitrite solution is added. The above addition is carried out over 75 minutes, maintaining the temperature below A chilled solution of 0.3 mole of stannous chloride in 75 m1. of concentrated hydrochloric acid is then added, dropwisc, to this stirred and cooled diazonium solution, over a period of three hours. During'thls addition the temperature is maintained at 0-5' and after the addition the solution is allowed to remain at 0' for several hours. The mixture is then filtered and the cake washed with cold sodium chloride solution. This solid is then added to 100 ml. of saturated acetate solution, extracted with ether and the ether dried. This crude 2-tluoro-4-methylphenylhydrazine is finally isolated and purified aslts hydrochloride.

When equivalent amounts of 3-lluoro-4-methylaniline, 2-lluoro-4-methoxyaailine. 3-lluoro-4-methoxyaniline, 2- fluoro-4-nitroaalline or 3-lluoro-4-nitroanlline is used in the above procedure in place of 2-fluoro-4-methylaniliae, there is obtained 3-lluoro-4-methy1phenylhydrazine, 2- fluoro-4-methoxyphenylhydrazlne, 3 tluore-4-methoxyphenylhydrazlne, 2 fluoro-4-nitrophenylhydrazine or 3- tluoro-4-nltrophenylhydrazlne, respectively.

EXAMPLE 49 MethyH or 6-fluoro3-lndolyl acetate 0.07 mole of 3-iluorophenylhydrazine and 0.08 mole of methyl-'m-dimethoxybutyrate are added to 250 ml. of 2 hi ethanolic hydrogen chloride and the mixture warmed until reaction sets in. tion stops, the mixture is refluxed for about one-half hour and then concentrated in vacuo to about one-third volume. Four hundred ml. of water are added and the aqueous solution extracted with ether. The ether extracts are washed with sodium bicarbonate solution, water, and then dried over sodium sulfate. The ether solution is concenp trated to a small volume in vacuo and chromatographed After the initial exothermic reac-.

ver 200 g. of acid-washed alumina. The material is lutccl with ether-petroleum ether (v./v. 50-60%) and istilled in a-short-path distillation apparatus. Both isolCl'S, namely, methyl-4-l'luoro-3-indoiyl acetate and tethyl-6-lluoro-3-indolyl acetate are obtained. The strucms of these two isomers are differentiated by means of uclear magnetic resonance spectroscopy.

When an equivalent amount of 3-liuoro-4-methylhenylhydrazine or 3-ilnoro-4-methoxyphenylhydrazine is mployed in place of 3-iluorophenylhydrazine, there is obllilCd both isomers of each, namely, methyi-(4-iluoro-S- tethyl- 1-indolyl) acetate. methyl-(6-liuoro-S-methyl-3- idQlyU-acetnte: or methyl-(d-tluoro 5 methoxy-Ii-inolyi)-acctate, methyi-(6-tluoro-5-methoxy-3-indolyl) acette, respectively.

Similarly, when an equivalent amount of 2-lluorophenylydrazine, 2-iluoro-4-mcthylphenylhydrazine or Z-lluoromethoxyphenylhydrazine is employed in place of 3- uorophcnylhydrazine, there is obtained methyl-(7-fluoro -indolyl) acetate, methyl-(7-tluoro-5-methyi-3-indolyl)- eetatc or methyl (7-tluoro5-methoxy-3-indolyl)-aeetate, espectively.

EXAMPLE 50 Methyl 1:;[4 or 6-[iuoroJ-Indoiyilpropionare When the procedure oi Example 49 is following, using iethyl--y,-y-dimethoxy-e-methyl-butyrate in place of meth= l-yq-dimethoxybutyrate, there is obtained two isomers, amely, methyl-a-( t-iluoro 3 indolyl)-propionate and 1ethyl--(6-iluoro-3-indolyl)-propionate.

When an equivalent amount of 3-lluoro-4-methylphenylydrazinc, 3-tluoro-4-methoxyphenylhydrazine or 4-nitrohenylhydrazine is employed in place of 3-lluorophenylydrazine, there is obtained both isomers of each, namely, iethyl a (-t-lluoro-S-metnyi 3 indolyl)-propionatc, rethyl a (6 fluoro-S-mcthyl-S-indolyl)-propionate; sethyl-e-(4-iluoro 5 methoxy-S-indolyl)-propionate iethyia-t6-fluoro-S-methoxy-B-indolyl) propionate; or iethyi-e-(4-fluoro-$-nitro-3-indolyl)-propionatc, methyl- -(6-tluoro-S-nitro-3-indolyl)-propionate, respectively.

Similarly, when an equivalent amount of 2-tluorophcnlhydrazine, 2-iluoro 4 methylphenylhydrazine, or 2- uoro-4-methoxyphenyihydrazine is employed in place of -tluorophenylhydrazine, there is obtained methyl-e-(7- uoro-B-indolyl) propionnte, methyl-mt7-iluoro 5-methi-3-indoiyl) propionate or mcthyl-a-(7-iluoro-5-methxy-J-indolyi)-propionate, respectively.

EXAMPLE 5 l Illa/'14 or 6 liuoro-2-mrthy-[-3-indoIyI-ncclates When the procedure of Example 49 is followed, using ietltyl lcvulinate in place oi methylmrdimethoxybutyrte, there is obtained two isomers, namely, methyl-(4- uoro-2-methyi-3-indolyl)-acetate and methyl-(6-iluoro- -methyi-3-indolyl )-acetatc.

when an equivalent amount of JIluoroJ-methylphenylydrazine or 3-tluoro-4-methoxyphenyihydrarine is cmloyed in place of J-Iluorophenyihydrazine, there is ob lined both isomers of each, namely, methyl-(2-S-dimethl-t-iluoroJ-indolyl)-ncetate, methyl 12,5 dimethyl-6- uoro-3-indolyl)-acetatc, or methyl-(4-iluoro-5-methoxy- -methyl-3-lndolyl)-acetate, methyl-(6-iluoro-$-methoxy- ,-methyl-3-indolyl)-acetate, respectively.

Similarly, when an equivalent amount of 2-iluorophenlhydrazine, Z-IluoroA-methylphenylhydrazine, Z-tluoro- -methoxyphcnylhydrar.ine, or 2-iluoro-4-nitm-phenylhyrazinc is employed in place of J-tluorophenylhydrazlne, here is obtained methyl-(7-iluoro-2-methyl-3-indolyl)- cetate, methyl-(2,5-dimcthyl-7-iluoro-3-lndolyi)-acetatc. ncthyl (7 tluoro methoxy 2 methyl 3 inolyl)-acetate, or methyl-t7-lluoro'2-methyl-5-nitro-3- ndolyi)-acetate, respectively.

When the procedure of Example 49 is followed using nethyl-a-methyl lcvulinate in place of methyl-7,7-dimethoxybutyrate, there is obtained two isomers, namely, methyl a (4 iluoro 2 methyl 3 indolyl) propionate and methyl-a-(6-iiuoro-2-met-hyl-3-indolyl)-propionate.

When an equivalent amount of 3-fluoro-4-methylphenylhydrazine or 3-iluoro-4-methylphenylhydrazine is employed in place of 3-iiuorophenylhydrazine, the-re is obtained both isomers of each, namely, met-hyl-a-(2,5-dimethyl-4-fluoro-3-indolyl)-propionate, methyI-a-(LS-dimethyl-6-iluoro-3-indolyl)-propionate; or methyl-e44- iiuoro-S-methoxy-2-methyi-3-indolyl)-propionate, methyl-- a (6 iiuoro 5 methoxy 2 methyl 3 indolyl)- propionate, respectively.

in addition, when an equivalent amount of 2-iluoro phenylhydrazine, 2-iluoro-4-methylphcnylhydrazine or 2- fluoroJ-methylphenylhydrazine is employed in place of Zi-fluorophcnylhydrazine, there is obtained mcthyl-a-(7- fluoro 2 methyl 3 indolyl) propionate, methyla-(2,3-dimethyl-7-fluoro-3-indolyi)-propionate or methylrs (7 fluoro 5 methoxy 2 methyl 3 indolyl)- propionatc, respectively.

A. A solution of 0.05 of a mole of methyl-(4-iiuoro- 3-indolyl)-acetatc and 0.01 of a mole of sodium in 60 ml. of bcnzyl alcohol is slowly fractionated over a period of 4% hours through a Vigreux column to remove methanol. The excess benzyl alcohol is then removed by distiliation at 60' C. (2.5 mm.) to give a residue of benzyl- (4-iluoro-3-indolyl)-acetate.

B. A suspension oi 0.046 m. of sodium hydridemineral oil in 250 ml. of dimethylformamide is stirred for 20 minutes under nitrogen with ice-cooling. Then 0.035 m. of the benzyl ester obtained above is added and the mixture stirred for 20 minutes. To the above mixture, 0.046 m. of thenoyl chloride in 50 ml. of dimeth= ylt'ormamide is added dropwise over a period of 30 minutes. The mixture is stirred in an ice-bath for 5 hours under nitrogen. it is then poured into a mixture of 500 ml. of ether, 5 ml. of acetic acid and l l. of iced water. The organic products are extracted with 3 x 300 ml. of ether. The ether solutions are combined and washed with a large quantity of water, and dried over sodium sulfate. The solution is filtered, evaporated to near dryness and the residue charged onto a 300 g. aluminn column. The crude benzyl-(l-thenoyl-4-fiuoro-3- indolyl)-acetate is eluted with ether-petroleum ether (5- 50% v./v.)..

C. 0.02 of a mole of the ester obtained in part B is added to 50 mi. of ethyl acetate containing a drop of acetic acid and is reduced eatalytleally at room temperature in the presence of palladium on charcoal catalyst. Upon completion of the reduction, the catalyst is removed by tlltration and the filtrate evaporated to yield (l-thenoyl-4-tluoro-3-lndolyl)-acetie acid.

EXAMPLE 53 a. to-sm'rnoxr-s-moonrr.)atomic ANHYDRIDE 0.049 mole of dieyclohexylcarbodlimide is dissolved in a solution of 0.10 mole of 6methoxy-3-indolyl acetic acid in 200 ml. tetrahydroi'uran and allowed to stand at room temperature for 2 hours. The precipitated urea is removed by filtration and the filtrate is evaporated in vacuo to a residue and tlushed with Skellysolve B. The residual oily anhydride obtained is used without purification in the next step.

It. (t-BUTYL-B-lttE'llt0XY-8-1NDOLYL)-ACETATE 2S mis. ot t-butyl alcohol and 0.3 gm. of fused zinc chloride are added to the anhydride from part A. The solution is refluxed for 16 hours and the excess alcohol is removed in vacuo. The residue is then dissolved in ether and washed several times with saturated salt solu tion. The ether extract is dried over magnesium sulfate and the solution treated with charcoal. The ether solu- 29 tion is then evaporated and flushed several times with Skellysolve B for complete removal of the alcohol. This residual oily ester is used without purification in the next step.

C. t-BUTYL-ll-(li-CllLOllO-2-TilENOYlsl-(l-METHOXY-fl- INDOLYLl-ACl-ITATH .065 mole of the crude ester, as obtained in step B, is added to 450 ml. of dimethyll'ormamide and cooled to 4' in an ice both. .098 mole of a 50% suspension of sodium hydride is added portionwise to this stirred soiu tion. After 15 minutes, 0.085 mole of 5-chloro-2-thcnoyl chloride is added over a l minute interval. This mixture is then stirred for nine hours, without replenish: ing the ice bath. At this time, the mixture is poured into 1 liter of acetic acid, extracted with a mixture of ether and benzene and washed thoroughly with water, sodium bicarbonate solution and a saturated salt solution. The ether extract is dried over magnesium sulfate, treated with charcoal and evaporated to a residue. The crude product, thus obtained, is chromatographcd on 600 g. of acid-washed alumina using a mixture of (v./v. 5-5096) ether-petroleum ether as eluent.

A mixture of 1.0 g. of the ester obtained in step C and 0.1 g. powdered porous plate is heated, with stirring, in an oil bath at 2l0 C. under nitrogen for 2 hours. The product is allowed to cool under nitrogen, then dip solved in benzene and ether, filtered and extracted with sodium bicarbonate solution. The aqueous solution is filtered by suction to remove ether. neutralized with acetic acid, then acidified weakly with dilute hydrochloric acid. The crude product'is then recrystallized from aqueous ethanol and dried in vacuo.

When the procedure of parts A, B, C, and D is used, starting with 7-methoxy-3-indoiyl acetic acid instead of the 6-methoxy isomer, there is obtained i-5-chloro-2- thenoyl-7-methoxy-3-lndolyl acetic acid.

EXAMPLE $4 I (S-clrloro-Z-lhcnoyl )-5,7-dimc'rhoxy-3-indolyl acetic acid mixture is then treated with charcoal and filtered through a sillcaceous tiller aid. The clear tiitrate is made alkaline with 400 mls. of dilute sodium hydroxide solution, and placed in a refrigerator, to cool. This mixture is then iilticred and the solid .gramine is washed with water-and dr ed.

ll. off-Dill B'lilOXY-lXDOLYL-S-ACEPOXITRILE 0.l06 mole of the gramlne obtained in A is added to 420 rnls. of methyl iodide, with vigorous stirring, over a period of minutes. The reaction mixture is then allowed to remain at S for 15 hours. The solution is filtered and the iodine metholate cake is dried at 50'. This solid is dissolved in a solution of 60 gm. of sodium cyanide in 1 liter of water and warmed for 2 hours at 80'. The desired product is extracted with chloroform which is then evaporated to give a crude oily product. The oil is then dissolved in 250 mls. of ether, filtered and 30 with petroleum ether, at which point the ,7dimethoxyindolyl-3-acetonitrile precipitates. The mixture ts then filtered and the cake dried.

C. 5,TDIlilETlIOXY-lN'DOLYL-(LACETIC ACID 0.08 mole of the nitrile obtained from B is added to a solution of mls. of alcohol, 100 ml. of water and 4.3 gms. of potassium hydroxide and refluxed for 15 hours. The mixture is brought to room temperature and 60 mls. of glacial acetic acid is added. The solution is then filtered through a tale filter and the filtrate diluted with $00 mls. of water. The precipitated 5,7-dimcthoxy-indolyl-3-acetic acid is then filtered and dried.

D. '1- WIILORO-iZ-THENOYL) -5,i-DIMETIIOXY-8- INDOLYL ACE'IIC ACID The procedure of Example 63A, 53B, 53C and 53D is followed using the product of part C of this example in place of the 6-methoxy-3-indolyl acetic acid, to produce l-(5-chloro-2-thcnoyl)-$,7 dimethoxy 3 indolyl acetic acid. When 5,6-dimethoxy-3-indolyi acetic acid is used in place of 6-methoxy-3-indoiyl acetic acid in the above procedure, there is obtained l-($-chloro-2-theaoyl)-$,6- dimethoxy-Ii-indolyl acetic acid.

When 5,6-methylenedioxyindole or 2-methyl-6-methoxyladole is used in place of 5,7-dimcthoxyindolo in the procedure of parts A. B and C, there is obtained 5,6- methylenedioxy-S-indolyl acetic acid, which, where used in the procedure of part D gives l-($-chloro-2-thenoyl)- $.6-methylenedioxy-3-lndolyl acetic acid or l-(S-chioro- Z-thenoyl)-2-methyl-6-methoxy-3-indolyl acetic acid.

EXAMPLE 5S Methyl-l-bcnzyloxy-J-indoiyi acetate A. d-BHNZYLOXY-S-IXDOLYL ACETONITRIIM B. METHYL 2(4-DENZYLOXI-INDOLYM)ACBTATB A mixture 0! OJ mole of (4-benzyloxy-indolyl-3)- acetonitrile in ml. of methanol, containing 30 grams dry hydrogen chloride, is refluxed for 2 hours. The reaction mixture is taken to dryness and the residue distributed between 1096 sodium bicarbonate solution and chloroform. The chloroform layer is dried with anhydrous sodiumsulfate and taken to drynessin vacuo. the residue is reasonably pure ester.

Similarly, when 7-benzyloxy-3-indolyl acetonitrile is used instead of the d-isomer, there is obtained methyl 7-benzyloxyl-3-indolyi acetate. When S-benzyioxy indole and G-benzyloxy indole are used in the procedure of part A and B of this example, there are produced methyl 5-benzyloxy-3-indoiyi acetate and methyl G-benzyloxy-S- lndolyl acetate.

EXAMPLE $6 ld-cliloro-s -lhcnoyl-l-melhoxy-d-lndoiyl acetic acid A. stm'rrrr. l-IIYDIIOXY-Q-INDOLYL *CBTATH A solution of methyl 4-benzyloxy-3-lndolyl acetate (4.0 g.) in 150 mi. methanol is shaken with 3 g. palladium I on charcoal and hydrogen until the hydrogen uptalte ceases. The catalyst is filtered and the filtrate is taken to dryness in vacuo.

D. METHYL l-Illi'lllOXY-ZHNDOLYL ACETATE the filtrate concentrated. This concentrate is then diluted 75 25-50%) as the eluent.

C. -i-.\iE'IilOXY-S-INUULYL ACETIC ACID A solution of methyl 4-methoxy-3-indoiyl acetate in excess 2 N absolute cthanolic potassium hydroxide is allowed to stand overnight, diluted with water and extracted with ether. The aqueous layer is acidified. The precipitate is collected and recrystallized from aqueous ethanol.

1). 1-5-CilLOltO-2-THENOYL-i-hiDTIIOXYdi-INDOLYL Act-.TtC ACID The procedure of Examples 53A, 53B, 53C and 53D is followed using the product of part C in place of 6-methoxy-B-indoiyl acetic acid, to produce l--chloro-2-thenoyl- 4-mcthoxy-3-indolyl acetic acid.

EXAMPLE $7 1-(5-clti0ro-2-llrenoyi)-5-cirioro-6-meiit0xy-3- indoiyi acetic acid A. (i-CHLOROti-hiETliOXY-ii-INDOLYL ACETIC' ACID When 5-chloro-6methoxy-3-indolyacetonitrile is used in place of 5, 7-dimethoxy-indolyl3-acetonitrile, in the procedure of Example 54C, there is obtained S-chloro- 6-methoxy-3-indolyl acetic acid.

a. 1-(5-CllL0lt0-2-TIXEXOYL)-0-ClIi.OR0-0-METHOXY-8- rxnomt. acra'rtc ACID When the procedures of Examples 53A, 53B, 53C and 530 are followed, using S choloro-6-methoxy-3-indolyl acetic acid as the starting material, there is obtained 1- (5chloro-2-thenoyl-5chloro-6-methoxy-3indolyi acetic acid.

When 2-methyl-7-mcthoxyindole is used in place of 5, 7-dimcthoxyindole in the procedures of Example 54A, 54B, and 54C and the product is used in the procedures of Examples 53A, 53B, 53C and 530, there is obtained l-(5-chloro-2-thenoyl) 2 methyl-7-methoxy-3-indolyi acetic acid.

EXAMPLE 58 I-(LehIoro-J-thenayi)-24nerhyi-4-merh0xy-3-indoiyi acetic acid A. 2-)! FZ'l'iiYiA-METIIOXYINDOLH (l) fi-melhaxy-Lniirobenzayl cItioride.0.0-i6 mole of 6methoxy-2-nitrobenzoic acid is added to 60 mls. of redistilled thlonyl chloride and refluxed for 2 hours. The excess reagent is removed under reduced pressure maintaining the temperature below 40'. The residue is washed with benzene and then removed under reduced pressure. The residue is placed over sodium hydroxide, in vacuo overnight.

(2) Diazomerlryi 6-mctiroxy-2-nitroplrenyiketone. A solution of .044 mole of the 6-methoxy-2-altrobenzoyl chloride obtained from l) in 30 mls. of dioxarre is added to a solution of 50mls. of diazonmethane in 200 ml. of ether, with agitation at 0'. The reaction mixture is allowed to remain overnight at room temperature. The solvent is then removed under reduced pressure to yield a residue containing the ketone. The 6-methoxy-2-nitrophenyl diazomethyl itetone is crystallized from this residue using dloxane.

(3) e-mcrhasy-z-nllroplrenylaeelic acld.-A solution of .044 mole of the diazoiretone obtained in (2) in 75 mls. of dioxanc, is added over a period of minutes to a freshly prepared solution of 4.0 gms. of silver oxide, 3.0 gms. of sodium thlosulfate and 5.0 mm. of sodium carbonate in 150 mls. of distilled water. The temperature of the reaction mixture is maintained at 50-60 during the addition and for an additional hour. At this point, the mixture is brought to a temperature of 90-95 for to hour. The mixture is then filtered and the filtrate is diluted with 200 mls. of water, acidified with dilute nitric acid and extracted with ehloriform (3 x 200 mls.). The combined chloroform extractis washed with 50 mls. of

water and dried over sodium sulfate. The chloroform is then removed and the residue extracted with boiling water (2 x 100 mls.). Concentration of the water solution, followed by cooling, precipitates the 6-methoxy-2- nitrophenyi acetic acid.

(4) ElIrci-d-mellroxy-Z-nitropitenyiacetyi maIonare.-- The product from A (3) is used in the procedure of part A (1) to give the corresponding acid chloride. A solution (0.02 mole) of this compound in 25 ml. of other is gradually added to a refluxing other solution of ethyl" ethoxymagnesiomalonate. Heating is continued until stirring is diilleult due to formation of a viscous oil. The cooled mixture is then shaken with dilute H (2.5 g. in 20 ml. H O) until the oily magnesium complex has dissolved. The ethereal phase is separated, washed with water, and dried over Na,SO Evaporation yields the crude clhyl-6-mcthoxy-2-nitrophenylacetylmalonate.

(5) 6-merlioxy-Zmilrophcnyiacerone.-A solution of 5.7 gms. of the product from A (4), l2 mls. of acetic acid, 1.5 mls. of sulfuric acid and 8 mls. of water is refluxed for 6 hours. The cooled solution is made alkaline with 5 N sodium hydroxide and extracted with ether (3 x 50 mls.). The combined ethereal extract is washed with water, dried over sodium sulfate and evaporated to give an oil which rapidly solidifies. Crystallization of this solid from ethanol yields 6-methoxy-2-nitrophenylaeetone.

(6) 4-melltoxy-2-nre!iryiind0ic.--l.2 gms. of the product from A (5) is added to a mixture of I00 mls. of ethyl alcohol and 1.0 gm. of Raney nickel. This solution is shaken at room temeperature and atmospheric pressure, in hydrogen for hour. The solution is then filtered and the filtrate evaporated under reduced pressure. Crystallization from light petroleum ether yields 4-methoxy- Z-methylindole.

B. Z-SZETIiYiri-MEl'iiOXY-a-INDOLYL ACI'YIXC ACID When 4-methoxy-2-methylindole is used in place of 5, 7-dimethoxyindole as described in Example 54A, 54B and 540, there is obtained 2-methyl-4 methoxy-3indolyl acetic acid.

C. 1-(5-CiiLOiiO-2-THE.\'OYL)-2-hiETiiYl'r l-METIIOXY-ii- IXDOLYL ACETIC ACID When the product from Example 588 is used in place of 6-methoxy-3-lndolyl acetic acid as described in Example 53A, 53B, 53C and 53D, there is obtained i-(S- chloro-Z-thenoyl) 2-methyl-4-methoxy-3-indolyl acetic acid.

EXAMPLE 59 I-(S-cirioro-Z-rlrenoyi)-7-metltoxyd-metltyI-J-indoiyl acetic acid A. 7-ETiiOXY-tS-hlETUYLiN-DOLE 0.1 mole of 4-metlryl-o-anisidine is added to 0.1 mole of monoehloroacetaldehyde and the mixture refluxed for 2 hours. The water formed is distilled off and the residue, is heated at 210-220 for an additional hour. This residue is then chromatographed on acid-washed aluminia and eluted with ether-petroleum-ether. The eluent is removed under reduced pressure and 7-methoxy-S-mcthylindole is obtained.

B. 1-(0-ClILORO-2-TUENOYL)-T-METiiOXY-5-METIIY[r3- l-NDOLYL ACETXC ACID The product from part A is used in the procedures of Example 53A, 53B, 53C and 53D. There is obtained 1- (5-ehloro-2-thcnoyi)-7-methoxy-5-methyl 3 indoiylacetic acid.

The procedures of parts A and B are followed, starting with 4-iluoro-o-anisidine, to give i-(5-chloro-2-thenoyl)-5- iluor0-7-mcthoxy-3-ind0lylacetic acid.

1-(S-chloro-Z-rlrenoyl)-2-allyi-S-metlroxy-3-indoiyi acetic acid A. li-ME'IHOXY-Z-XNDOLYL ACETALDBHYDE A solution of S-methoxy-2-indolylacetyl chloride (0.1

mole) in dry tetrahydrofuran is treated with 0.25 mole of lithium aluminum tri-t-butoxy hydride with ice-cooling and stirring. After the initial reaction, the mixture is stirred at room temperature for 4 hours and poured into ice. Excess of acetic acid is added and the product is extracted with ether. The ethereal solution is washed with sodium bicarbonate, dried over sodium sulfate and evaporated to a syrup. Chromatography of the residue on a column of silica gel, using ether-petroleum ether (v./v. l-30%) as eluent, gives S-methoxy-Z-indolyl acetaideh de.

y B. 2-.\LLYI.-li-METITOXY IXDOLE A solution of 0.1 mole of the aldehyde and 0.12 mole of methylene triphenylphosphine, prepared in situ from 0.12 mole of methyl trlphenylphosphonium iodide and 0.12 mole of n-butyi lithium, in benzene is stirred at room temperature for 4 hours and then at 80 for 1 hour. The solution is washed with 0.5 N hydrochloric acid, water and dried over sodium sulfate. Evaporation of the solvent in vacuo and chromatography of the residue on a column of 300 g. acid-washed alumina, using etherpetrolcum ether (v./v.) 0-2096 as eluent, gives 2-allyl-5- methoxy indole.

C. fl-ALLYIAi-METHOKYGRA)! in A solution of 0.032 mole of Z-aIlyl-S-methoxy indole in 40 ml. of dioxane is added dropwise, over 30 minutes, to an ice-cooled stirred mixture of 40 ml. dloxane, 40 ml. acetic acid, 3.2 ml. 36% aqueous formaldehyde and 8.8 ml. 25% aqueous dimcthylamine. The clear solution is stirred and cooled for two hours and then allowed to warm to room temperature overnight. To this solution is added 500 ml. of water. The turbid mixture isthen treated with charcoal and filtered through a sillcaceous filter aid. The clear filtrate is made alkaline with 400 mi. of dilute NaOH solution and cooled in a refrigerator. The

' mixture is filtered and the solid gramine is washed with water and dried.

D. 2-.UaLYlr6-XETHOXY4-IXDOLYL ACWIONITRXLE 0.106 mole of the gramlne from part C is added to 420 ml. of methyl iodide, with vigorous stirring, over a period of 20 minutes. The reaction mixture is then allowed to remain at 5' for hours. The solution is filtered and the iodine methoiate cake is dried at 50' C. The solid is dissolved in a-solution of 60 g. NaCN in 1 liter and warmed for 2 hours at 80'. The desired product is extracted with chloroform which is then evaporated to give a crude oily product. The oil is then dissolved in 250 ml. of ether, filtered and the filtrate is concentrated. The concentrate is diluted with petroleum ether, at which point the 2-allyl-S-methoxy-S-indolyl acetonitrile precipitates. The mixture is filtered and the cake dried.

0.08 mole of 2-allyl-S-methoxy-Il-indolyl acetonitrile is added to a mixture of 140 mi. of alcohol, 100 ml. of water and 4.3 g. of KOH. The mixture is refluxed 15 hours and then brought to room temperature. Glacial acetic acid (60 ml.) is added and the solution is filtered through a tale filter. The filtrate is diluted with 500 ml.

34 of water and the precipitated 2-allyl-5-methoxy-3-indolyi acetic acid is separated by filtration and dried.

F. 1-(5-CHIDRO-2- IHENOYL)-2-ALLYL-liM-E71HOXY-3- 'INDOLYL IACETIC .ACID

The procedures of Examples 53A, 53B, 53C and 53D are followed using the product of part E in place of the 6-methoxy-3-indolyl acetic acid, to produce 1-(5-chloro-2- thenoyl)-2-allyl-5-methoxy-3-indolyl acetic acid.

EXAMPLE 6i 1 (4-hydran -3-merhyI-2-rhenoyl )-2-merlryl-5-merhoxy- 3-indoiyi acetic acid A. METHYL-4-BENZYLOXY-8-M'EIHYU2-THENOATE To a solution of 0.02 mole methyl'4-hydroxy-3-methylthiophene-2-carboxylate in 100 ml. dimethylformamide is a ded 0.022 mole of potassium t-butoxide with ice-cooling and stirring. After one-half hour, 0.022 mole of benzylchloride is added and the mixture is stirred at 0-5 for 2 hours and then at room temperature for 18 hours. The solution is poured into water and extracted with ether. The product is chromatographed on 300 g. acid-washed alumina using ether-n-hexane (v./v.) 20-60% as eluent.

B. d-BENZYLOXYQ ME'IHYIrZ-THENOIC ACID The product of part A is stirred with excess 2 N NaOH in aqueous ethanol for 18 hours. The mixture is then diluted with water, filtered and acidified. The precipitated acid is filtered, washed and dried.

The product of part B (0.1 mole) is heated with excess ,thionyl chloride to 70' C. until reaction is substantially complete. The excess thionylchlorlde is removed by distillation in vacuo and the residue is picked up in dimethylformemide. This solution is then used in the procedure of Example 12A, in place of the methoxymethyl thenoyl chloride, to produce t-butyl l-(4-benzyioxy-3-methyl-2- thenoyl)-2-methyl-S-methoxy-Zi-lndolyl acetate.

1). t-u-nmtzrrsoxs a-atmttrrrs-rrn-txortn-s-armust.-

e-stu'ruoxrersoonrnacu'rrc atom The procedure of Example 128 is followed, using the product of part C, to yield the free acid.

The product of part D is hydrogenated in ethanollc solution at room temperature and 40 p.s.i. over a 10% palladium on charcoal catalyst until the reaction is substantially completed. The catalyst is removed by filtration and the solution is evaporated to dryness in vacuo. The residue is chromatographed on a silica gel column using ether-ethyl acetate as the eluent, to give l-(4-hydroxy 3-methyl-2-thenoyl)-2-methyl-S-methoxy-B-indolyl acetic acid.

' EXAMPLE 62 Methyl-ll-(S-nllro-Z-tltenoyl)-2-methyi-5-methoxy- .i-Indolyllacetate EXAMPLE 63 Methyl- I 3 -dimerhyiamino-2-ihenayl -2-merhyl- 5-metIroxy-3-lndolyi1acetale The procedure of Example 19 is followed, using the product of Example 62 in place of the indole ester used therein, to produce methyl [l-(S dimethylamino 2- thenoyl)-2-mcthyl5methoxy-3-ind0lyl]acetate.

EXAMPLE 64 M crh yl- 1 -amino-2-rlrenoyl -2-mcrlryI-5 -metlr0xy- 3-r'nd0iyl1acclate The procedure of Example 23 is followed using the product of Example 62 in place of the indole ester used To 4.3 moles of a solution of n-butyl lithium in henmne. under nitrogen. is added 1.0 g. of Z-t'iuorothiophene in 4 cc. of dry ether. The mixture is stirred at room temperature over night and then poured on dry ice. it is acidiiled with 2.5 N HCl and extracted with ether. The ether solution is then extracted four times with saturated aqueous NaHCO,. The bicarbonate solutions are acidified with concentrated HCl which has been diluted with an equal volume of water and extracted with ether. The ether solution is washed with water and dried over MgSO after which it is concentrated to dryness, giving 645 mg. of i-iluorothenoic acid, MP. 135- 140. This product is treated with charcoal in ether solution and recrystallized from ether several timcs. it is finally'sublimcd at 80'. MP. 139-141.

Calc.: C. 41.11; H. 2.07; 8. 21.95; F, 13.00. Found:

c. 41.44; a, 2.4; 5. 21.82; F, 12.4. pKia 50% aqueous methanol 4.3.

11. B-FLUOllO-fl-THENOYL CIIIJORIDB 5tluoro-2-thenoie acid is retluxed with thionyl chloride in benzene solution with azeotropic removal of byproduct water until the reaction is substantially complete. The solvent and excess thionyl chloride are removed by distiliation in vacuo to leave a residue of idluoro-Z-thenoyl chloride.

srrrrtroXY-a-rxnomnlACETATE The procedure of Example 3 is followed using S-liuoro- Z-thenoyl chloride in place of S-chloro-2-thenoyl chloride to give methyl-[l-(S tluoro w 2 thenoyl)2-methyl-5 methoxy-S-indolyllacetate.

1 claim:

1. A compound 01 the formula its 1: Jill-C 011 n N 11: a Jf ltr (iii

phenylsulfonyl, lower alkylsulfonyl, phenylthio, benzylthio lower alkyl, benzyl sulfonyl lower alkyl, lower alkylthio lower alkyl, benzyloxy lower alkyl, furfurylthio lower alkyl, nitro, amino, di-(lower alkyl)amino, lower alltylamino lower alkanoylamiao, hydroxy, and benzyloxy;

R, is selectedfrom the group consisting of hydrogen,

lower alkenyl and lower alkyl;

R; is selected from the group consisting of hydrogen I and lower alkyl;

R is selected from the group consisting of hydrogen, lower alkyl. lower alkoxy, fluorine and triiluoromethyl;

R is selected from the group consisting of hydrogen, hydroxy. lower alkyl, lower aiitoxy nitro, amino, lower alkylamino, di(lower alkyl) amino, lower alkanoyiamino, lower alitanoyl, lower alkylamino, bis(hy-= dr xy lower alkyl)amino, l-pyrrolidino, 4-methyl-= l-piperizinyl, 4-morpholinyl, eyano, amino lower alkyl. di-lower alkyl amino, lower alityl, triiluoromethyl, halogen, di(lower alkyl)suli'amy1, benzylthio, lower aikylbenzylthio, lower alkoxybenzylthio, halogenobenzylthio, benzyloxy, lower alkylbenzyloxy, lower nlkoxybenzyloxy, halogeno-benzyioxy. lower alkenyl, lower alkenyloxy. l-azacyclopropyl, cyclopropyl(lower alkoxy)methyloxy, and cyclobutyltlower nlkoxy)- methyloxy and M is selected from the group consisting of 0H, Nii

benzyloxy, lower alltoxy, 02 where Z is a cation selected from the group consisting of alkali metals, allta= line earth metals, aluminum, iron, magnesium, methyl ammonium, methyl cyclohexyl ammonium, morpholinium and glucose ammonium and CY where Y represents the structure 2. A compound of the formula li -CO O U in which R, and R; are each lower alkyl and R is lower allroxy.

J. A compound of the formula its Air

in which R; and R; are each lower alltyl and R is lower alkoxy.

37 4. A compound of the formula R: In 4111-0001! in which R,. R, and R, are each lower alkyl.

5. A compound of the formula R: R HI-COOII Ra N in which R,. R, and R, are each lower allryl.

6. A compound of the formula in which R, is lower alkyl and R, is di(lower alkyl)- amino.

8. A compound of the formula 5 R CHr-COOII Ra N in'which R, is lower alkyl and R, is lower alkoxy. 9. A compound of the formula R CH|COOII R N I in which R, is lower alkyl and R, is di(lower alkyl) amino.

10. a Il-(2'-thenoyl)-2-methyl-5'methoxy-S-indolyl1 propionic acid.

11. a ll-(S-chloro-bfuroyl)-2-methyi-5-methoxy-3 lndolyll-propionic acid.

12. l (S-lluom-Z-thenoyi)-2-methyl-5-methoxy-3-in dolyl-aoetic acid.

13. a [l-(S-chioro-2-lhenoyl)-2-methyi-5-dimethyla mino-3-indolyl1-acetic acid.

14. l (5-chloro-2-furoyl)-2-methyl-5-dimethylamino 3-lndolylacetic acid.

15. l (5-chloro-2-furoyl)-2-methyl-S-methoxy-3-indo lyl acetic acid.

16. l (l-methylpyrryl)-2'methyl-5 methoxy-3-lndoly acetic acid.

References Cited by the Examiner UNITED STATES PATENTS I 2,80l,908 8/57 Middleton 260322." 2,92l.076 l/62 Pareell 260-293. 3,05 L723 8/62 Fritz 260-3 l 3,067,206 12/62 Krnlt et al. 260-31 3,093,657 6/63 Schor'r el al. 260332.'

NICHOLAS S. RlZZO, Primary Examiner. 

1. A COMPOUND OF THE FORMULA 